1 Introduction

Recently, the mortality rates of many cancer types have decreased [1]; however, those of liver cancer have increased in both men and women [2]. This concern highlights the need for proactive strategies to prevent, treat, and combat chemoresistance. Hepatocellular carcinoma (HCC), the most common type of primary liver cancer, shows somatic DNA changes, such as mutations and chromosomal aberrations [3]. The major risk factors for HCC include chronic liver diseases, particularly metabolic dysfunction-associated steatotic liver disease (MASCD, early stage), non-alcoholic steatohepatitis (NASH, late stage), and Hepatitis B and C virus (HBV and HCV, respectively) infections [4]. These conditions create a unique tumor microenvironment in HCC and influence mitochondrial function.

Different regions of hepatocytes in the liver perform different functions. Factors such as oxygen, nutrients, and microorganisms control the regions around the central and periportal veins, forming the basis of standard liver function [5]. Hepatocytes contain more mitochondria than those in other cell types [6]. Hepatic mitochondria produce energy through oxidative phosphorylation (OXPHOS) to generate adenosine triphosphate (ATP) [6]. Under pathological conditions, hepatocytes in different regions respond differently to injury. HCC may utilize the Warburg effect to rapidly obtain ATP via glycolysis, thereby promoting hepatocarcinogenesis, growth, and metastasis [7]. In proliferating hepatocytes exhibiting the Warburg effect, the mitochondrial metabolic pathways become saturated. This leads to increased glucose consumption by HCC cells. This metabolic change allows hepatocytes to efficiently convert nutrients, such as glucose and glutamine, into biomass, preventing their oxidation into CO2 and preserving carbon bonds for anabolic processes [8]. In addition, mitophagy reduces the mitochondrial network, thus enhancing the conversion of glucose to lactate via glycolysis [9]. Alterations in mitochondrial metabolism, imbalances in mitochondrial dynamics, and hypoxic tumor microenvironment are closely linked to hepatocarcinogenesis and the metastasis of HCC [10,11,12]. Mitochondria can also adapt to tumor conditions, potentially evolving into "oncogenic mitochondria" which transfer malignant capabilities to recipient cells [13].

Damaged mitochondria release mitochondrial DNA (mtDNA) and cytochrome C into the cytoplasm, thus activating damage-associated molecular patterns (DAMPs) and triggering chronic inflammatory responses [14] (shown in Fig. 1). Mutations in tricarboxylic acid (TCA) cycle enzymes can also promote malignant transformation [15]. The accumulation of substances caused by mutations in isocitrate dehydrogenase as well as cancer-related gene mutations or protein expression can lead to carcinogenesis [15]. The following processes help remove damaged mitochondria: mitochondrial dynamics (fusion and fission), mitophagy, pyroptosis, ferroptosis, and cuproptosis [9, 16]. However, unregulated mitochondrial dynamics or excessive damage reduces the number of normal mitochondria. Mitochondrial biogenesis, which facilitates the formation of new mitochondria, requires the regulation of both nuclear and mitochondrial genes to maintain optimum intracellular mitochondrial homeostasis [17]. Additionally, chemoresistance poses a significant challenge in treating patients with HCC, owing to its potential association with changes in mitochondrial function. This review examines the impact of changes in hepatic mitochondrial function on HCC and mitochondria-associated chemoresistance.

Fig. 1
figure 1

Mitochondrial pathways in Hepatocellular Carcinoma (HCC) pathogenesis. During HCC development, increased mitochondrial activity leads to increased reactive oxygen species (ROS) levels. This induces antioxidant systems such as NAD+-dependent deacetylase sirtuin-3 (SIRT3) and superoxide dismutase 2 (SOD2), to neutralize reactive oxygen species (ROS). However, continuous ROS accumulation lowers mitochondrial efficiency, activates AMP-activated protein kinase (AMPK) and proliferator-activated receptor γ coactivators 1-α (PGC-1α) transcription mechanisms, and triggers the expression of mitochondrial adaptive gene pathways. Abnormalities in mitochondrial unfolded protein response (mtUPR) can also promote the occurrence and hepatocarcinogenesis of HCC. Normally, damaged mitochondria are cleared via mitophagy; however, lipid accumulation hinders this process. If mitophagy is blocked, the damaged mitochondria split and release inflammatory damage associated mitochondrial molecular patterns (DAMPs) and cytochrome C, thus driving hepatocarcinogenesis. Temporal alterations in lipid metabolism, one-carbon metabolism, and amino acid biosynthesis trigger compensatory proliferation of cancer cells, further intensifying hypoxia, DNA damage, mutations, and evasion of cell cycle checkpoints. The X proteins include Forkhead Box O3 (FoxO3), Isocitrate Dehydrogenase (NADP+) 2 (IDH2), Pyruvate Dehydrogenase (PDH), NADH:Ubiquinone Oxidoreductase Subunit A9 (NDUFA9, Complex I), and Succinate Dehydrogenase Complex Flavoprotein Subunit A (SDHA, Complex II). Ac, acetylated; ATP, adenosine triphosphate; BNIP3, BCL2 interacting protein 3; ER, endoplasmic reticulum; ERR, estrogen-related receptor; HCC, hepatocellular carcinoma; HMGB1, high mobility group box 1; JNK, c-Jun N-terminal kinase; LC3, microtubule-associated protein 1A/1B-light chain 3; IL1α, interleukin 1α; mtDNA, mitochondrial DNA; NIX, NIP3-like protein X; NRF1/2, nuclear respiratory factor 1/2; P62, p62/SQSTM1; PAMPs, pathogen-associated molecular patterns; PINK1, PTEN-induced kinase 1; PPAK, peroxisome proliferator-activated receptor; Ub, ubiquitin. "↑" represents an increase, while "↓" represents a decrease. The arrow symbolizes promotion, while the blunt line represents inhibition

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1.1 HCC: Mitochondrial metabolism and dysfunction

Oxygen levels vary in different parts of the liver, leading to unique mitochondrial characteristics in the periportal and pericentral regions [18]. In the periportal region, mitochondria primarily engage in processes, such as amino acid metabolism, glycogenesis, glycolysis, phosphorus oxidation, and exogenous metabolism within the inner mitochondrial membrane or matrix [18]. Lower oxygen levels in perivenous regions can trigger the activation of WNT/β-catenin signaling through hypoxia-inducible factor-1α (HIF-1α), which is involved in proliferation, dedifferentiation, epithelial–mesenchymal transition (EMT), migration, invasiveness, and metabolism [19]. Reactive oxygen species (ROS) can stabilize HIF-1α and activate glycolysis, promoting the Warburg effect and hepatocarcinogenesis [7, 11]. The hepatic urea cycle occurs in the mitochondria and cytosol of periportal hepatocytes and converts toxic ammonia into non-toxic urea [6, 20]. Mitochondria in the periportal hepatocytes also metabolize hepatic fatty acids through β-oxidation [6]. During energy deficiency, fatty acid metabolism exceeds energy needs, leading to excess acetyl- coenzyme A (CoA) entering the ketogenic pathway [21], resulting in the formation of ketone bodies and a reduction in gluconeogenesis [22]. Consequently, HCC adapted to hypoxic environments are more likely to originate from the periportal region [20].

1.1.1 Oxidative stress, ROS, and hypoxia

HCC is often associated with oxidative stress and DNA damage (shown in Fig. 1). Oxidative stress occurs when there is an imbalance between oxidants and antioxidants, resulting in disrupted redox signaling, impaired cellular control, and potential molecular damage [23]. In oxidative stress, the concentration of oxidants greatly exceeds that of antioxidants, thus impairing mitochondrial function. This imbalance causes oxidative stress in the mitochondria and nuclei, which initiates DNA damage and apoptosis [24]. Glutathione (GSH), a water-soluble antioxidant containing a thiol group, interacts with glutathione peroxidase (GPx) to convert organic peroxides into hydroxyl groups and water. During this process, GSH is converted into glutathione disulfide (GSSG) [23]. Following HCC recurrence, patients show significantly lower levels of plasma malondialdehyde and increased levels of GSH, GSSG, antioxidant capacity, and enzyme activities (GPx and glutathione reductase) relative to those of their non-recurrent measurements [25]. In patients with both recurrent and non-recurrent HCC, the levels of GSH, Trolox equivalent antioxidant capacity, and GPX activity in the cancerous regions are significantly higher than those in the adjacent normal regions [26]. In addition, proto-oncogene c-Myc overexpression in hepatocytes stimulates the production of mitochondria-associated membranes, triggering the release of Ca2+ from the endoplasmic reticulum to the mitochondria. This causes oxidative stress and inhibits OXPHOS in the hepatocytes, thereby facilitated hepatocellular carcinoma initiation [27]. Increased oxidative stress causes the accumulation of antioxidants, which contributes to hepatocarcinogenesis and cancer recurrence.

ROS can have either beneficial or harmful effects, depending on their concentration. ROS control various cellular processes including differentiation, immunity, tissue regeneration, and aging. They also aid in cell signal transmission, thus influencing the expression of nuclear genes [28]. Cellular ROS levels steadily increase from the G1 phase to the S phase, and then to the G2 phase [29]. ROS stimulates HCC cell proliferation through phosphoinositide 3-kinase-mediated AKT phosphorylation [30]. Additionally, osteopontin enhances hepatocarcinogenesis by initiating Janus kinase 2/signal transducer and activator of transcription 3 (STAT3)/NADPH oxidase 1 (NOX1)-mediated ROS generation and increasing NOX1 expression [31]. Thus, excessive ROS generation in hepatocytes may promote hepatocarcinogenesis.

The hypoxic tumor microenvironment triggered ongoing activation of mechanistic target of rapamycin (mTOR)-dynamin-related protein 1 (Drp1), causing excessive mitochondrial fission into fragments [32]. Mitochondrial transfer enhances the migration and invasion of less-invasive HCC cells (derived from highly invasive cells) grown under hypoxic conditions [33]. Specific mitochondrial proteins regulate metabolism and trigger hypoxia. Sirtuin (SIRT)−3 inhibits cell growth, reduces extracellular acidification rates, increases oxygen consumption, and controls metabolism through acetylation and deacetylation (shown in Fig. 1) [34]. It lowers the levels of hexokinase 2 and pyruvate kinase M2, enhances mitophagy signaling, and upregulates the associated proteins. SIRT3 also elevates peroxisome proliferator-activated receptor γ (PPARγ) coactivator 1α levels and mtDNA quantity while decreasing intracellular ROS levels [34]. Furthermore, it maintains the intracellular calcium balance by regulating sarcoendoplasmic reticulum calcium ATPase activity, prevents calmodulin-dependent protein kinase II (CaMKII) activation, and preserves F-actin through the CaMKII/cofilin pathway. This process maintains the lamellipodia and promotes HCC metastasis [35]. Additionally, mitochondrial transfer helps cells handle various types of stress, including metabolic changes, oxidation, and DNA damage, by maintaining a stable cellular balance and communication within tissues [36]. When mitochondria move from highly invasive to less invasive ones, they enhance the ability of recipient cells to migrate and invade [33]. Under hypoxic conditions, high mobility group protein 1 (HMGB1) increases the expression of Ras homolog family member T1 (RHOT1) and Rac family small GTPase 1 (RAC1) in HCC cells. This is related to the formation of tunneling nanotubes, which stimulate migration, invasion, and mitochondrial transfer in HCC cells [33]. Patients with HCC exhibiting high expression levels of HMGB1, RHOT1, or RAC1 typically experience relatively shorter overall survival [33]. Hypoxia in hepatocarcinogenesis increases mitochondrial transfer and cancer cell migration and invasion, thus worsening HCC severity.

1.1.2 Failure of the mitochondrial unfolded protein response mechanism

Majority of the mitochondrial proteins are encoded in the nucleus and then refolded within the mitochondria. Oxidative stress-induced ROS generation can lead to the accumulation of misfolded or unfolded proteins in the mitochondrial matrix, initiating a mitochondrial unfolded protein response (mtUPR) [37], which degrades misfolded or unfolded proteins. mtUPR regulates mitochondrial proteostasis through a transcriptional response which boosts chaperone expression when unfolded or misfolded proteins build up in the mitochondria [38]. In addition, mtUPR activates other proteins such as proteases and plays a role in various conditions, including cancer [37, 39]. Activation of mtUPR triggers nuclear translocation of activating transcription factor 5 (ATF5) [38]. Phosphorylation of the eukaryotic translation initiation factor 2α leads to ATF5 overexpression [38]. This initiates the transcription of mtUPR-related genes, including heat shock proteins (HSP) 60 and 10, and ATP-dependent Lon protease (LONP1). These proteins are then transported to the mitochondria [40, 41]. Within the mitochondrial matrix, molecular chaperones, such as HSP10/HSP60 and HSP70, can refold misfolded or unfolded proteins. Alternatively, these proteins can be cleaved by mitochondrial proteases such as LON and mitochondrial casein [40, 41], or degraded by mitochondrial casein peptidase P, a serine protease located in the mitochondrial matrix [42]. Misfolded or unassembled proteins in the mitochondrial inner membrane, particularly unassembled OXPHOS subunits, are mainly cleaved by the i-AAA/m-AAA membrane-integrated protease system and related AAA proteases [41]. Misfolded proteins in the mitochondrial outer membrane (MOM) are ubiquitinated by the cytoplasmic ubiquitin–proteasome system (UPS) and subsequently degraded [37]. Globally, China has the highest rate of HBV-related HCC, accounting for approximately 65% of all cases, while the rates in America and Europe are less than 20% [43]. In patients with HBV-related HCC, miR-148a levels are reduced because HBx suppresses p53-mediated miR-148a activation [44]. Through mTOR signaling inhibition, miR-148a decreases tumor growth, EMT, invasion, and metastasis in both HBx-expressing hepatocarcinoma cells and mouse models [44]. HBx interacts with the mtUPR chaperones HSP10/HSP60 and HSP70 [45], which enhance HBx-mediated apoptosis [46]. HBx triggers mtUPR, leading to the relocation of LONP1 from the cytoplasm to mitochondria. Activation of the LON/PTEN-induced kinase 1 (PINK1) pathway promotes mitophagy and inhibits apoptosis [47]. HBx damages mitochondrial structure of hepatocarcinoma cells by triggering PTEN/parkin-mediated mitophagy [48]. These changes disrupt membrane potential and ROS production, with different genotypes causing varying degrees of mitochondrial damage [48]. Furthermore, HBx increases α-fetoprotein levels and promotes hepatocarcinogenesis [49]. The E3 ubiquitin protein ligase MARCH5 facilitates the degradation of HBx via the UPS. This process reduces HBx-induced inflammation by suppressing ROS generation. MARCH5 activity decreases progressively with increase in HCC grade. Increased MARCH5 activity positively correlates with extended survival in patients with HCC [50]. Failed clearance of misfolded proteins or abnormal viral proteins by mtUPR leads to mitochondrial abnormalities, triggering cell death mechanisms, and promoting HCC progression.

1.1.3 Failure of de novo hepatic lipogenesis

De novo hepatic lipogenesis is a process in which the liver generates new fatty acids from acetyl-CoA. Mitochondrial OXPHOS complex I and NADH: ubiquinone oxidoreductase subunit B3 are linked to ROS generation in the fatty acid oxidation pathway [10]. Glycogen degradation helps eliminate ROS, whereas fatty acid oxidation contributes to ROS production. The liver maintains lipid balance through mitochondrial fatty acid oxidation, de novo lipogenesis for fatty acid synthesis, and lipoprotein secretion and intake [51]. Fatty acids and lipids serve as essential signaling factors, energy sources, and cell membrane components and play vital roles in cell growth. Upregulated de novo lipogenesis contributes significantly to MASCD [52] and HCC development [53]. In the de novo lipogenesis pathway, citrate is sequentially converted to acetyl-CoA, malonyl-CoA, and palmitic acid, a process catalyzed by ATP citrate lyase (ACLY), acetyl-CoA carboxylase (ACC), and fatty acid synthase (FASN). Following elongation, stearoyl-CoA desaturase (SCD) transforms saturated fatty acids into monounsaturated fatty acids, which are the preferred building blocks for triglyceride formation [54]. MASCD, mainly caused by abnormal lipid accumulation in the liver, often results in swollen mitochondria and reduced cristae activity [55]. Increased levels of ACLY, ACC [56], FASN [53, 57], and SCD [58] correlate with poor outcomes in patients with HCC. The critical regulator of de novo fatty acid synthesis, ubiquitin-specific protease 22, stabilizes PPARγ through K48-linked deubiquitination. This process increases the expression of ACC and ACLY, thereby promoting hepatocarcinogenesis [59].

Mitochondria function to maintain normal fatty acid β-oxidation, which helps counter alcohol-induced hepatic lipid accumulation and steatosis [60]. Alcohol intoxication increases hepatic mitochondrial cytochrome P450 (CYP) 2E1 levels, leading to excessive ROS generation. These substances, along with acetaldehyde and free radicals, deplete reduced GSH. This results in lipid peroxidation and mitochondrial dysfunction, ultimately leading to liver damage [61]. However, prolonged exposure to alcohol disrupts mitophagy, leading to the release of DAMPs [60]. On entering the cytoplasm and extracellular environment, these molecules stimulate liver inflammation and fibrosis [60]. Patients with NASH-derived HCC exhibit elevated expression of steroid acute regulatory protein 1 (STARD1), which affects CYP27A1-regulated mitochondrial pathways, thereby promoting NASH-driven HCC [62]. In addition, serine/threonine protein kinase 25 (STK25) plays an important role in regulating glucose and insulin homeostasis and ectopic lipid accumulation. The knockdown of STK25, which participates in autophagy, cell polarity, apoptosis, and migration, can improve the proliferation, migration, and invasive capabilities of HCC cells [63]. Abnormal lipid synthesis and metabolism can lead to hepatic mitochondrial dysfunction and promote chronic liver diseases and hepatocarcinogenesis.

1.2 Failure of mitochondrial dynamics mechanism in hepatocarcinogenesis

Mitochondrial dynamics, which involves fusion and fission processes, play a critical role in maintaining the quantity and quality of mitochondria by eliminating damaged mitochondria (shown in Fig. 2) [64]. Changes in mitochondrial morphology are associated with cell cycle progression [65]; mitochondrial dynamics also affect the cell cycle and cell proliferation [65]. During the G1/S transition, mitochondria transform from separate fragmented units into large interconnected networks. This network maintains electrical continuity and produces more ATP than that by mitochondria in other cell cycle phases [66]. This includes changes in the shape of the mitochondrial network during G1/S transition and significant fragmentation during cell division. The extended "hyperfusion" network during the G1/S phase is associated with increased ATP production, which prompts cells to enter the S phase by regulating cyclin E levels [66]. When mitochondria are depolarized in early G1, cells cannot progress from the G1 to S phase [66]. Mitochondrial process protein 1, which contributes to mitochondrial fission, leads to an increase in mitochondrial debris, participates in the G1/S transition, inhibits apoptosis, and promotes HCC proliferation [67].

Fig. 2
figure 2

Mitochondrial dynamics during cell cycle progression. During the G0 phase, mitochondria undergo fusion, fission, and depolarization. Mitochondrial fusion proteins 1 and 2 (MFN1/2) and optic atrophy 1 (OPA1) facilitate mitochondrial fusion. Mitochondrial fission relies on dynamin-related protein 1 (DRP1) and mitochondrial fission factor (MFF). Eventually, fragmented and dysfunctional mitochondria are discarded via mitophagy. The mitophagy receptors BCL2 interacting protein 3 (BNIP3) and NIP3-like protein X (NIX) bind to microtubule-associated protein 1A/1B-light chain 3 (LC3), associating mitochondria with autophagosomes. PTEN-induced kinase 1 (PINK1) accumulates on the surface of depolarized mitochondria and phosphorylates ubiquitinated mitochondrial outer membrane proteins, including parkin, which further promotes ubiquitination of these proteins. The p62/SQSTM1 link recognizes ubiquitinated proteins and triggers mitophagy. In different phases of the cell cycle, mitochondria undergo hyperfusion during the G1-S phase, fragmentation during the S phase, and dispersion during the M phase. FIS, mitochondrial fission protein; OXPHOS, oxidative phosphorylation; ROS, reactive oxygen species; Ub, ubiquitin. "↑" represents an increase, while "↓" represents a decrease. The arrow symbolizes promotion

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1.2.1 Abnormalities in mitochondria fusion

Mitochondrial fusion reduces the damage to mtDNA, proteins, and lipids by homogenizing and diluting the mitochondrial matrix and membranes [68]. In liver cancer, mitochondrial fusion decreases tumor cell oxygen consumption and ATP production, where increased mitochondrial fusion alters metabolism and fuels tumor cell growth [69]. Mitochondrial fusion involves two key proteins, mitofusin (MFN)1 and optic atrophy-1 (OPA1). MFN1 facilitates fusion of two mitochondrial outer membranes by docking through the HR2 or GTPase domains, thus promoting GTP hydrolysis [68]. In contrast, OPA1-mediated fusion depends on the mitochondrial inner membrane potential and helps maintain mitochondrial function and integrity [64]. In HCC, high MFN1 levels reduce aerobic glycolysis, stimulate OXPHOS activity, and inhibit HCC proliferation and invasion [12], leading to longer progression-free and overall survival [12]. Conversely, lower MFN2 levels in HCC and surrounding tissues are associated with shorter overall survival [70]. Excessive MFN2 can cause cell cycle arrest and suppress cell proliferation [71]. Low OPA1 levels increase mitochondrial fusion and OXPHOS activity, thereby promoting HCC proliferation [69]. Decreased OPA1 levels can also lead to mitochondrial fragmentation and the release of cytochrome C, ultimately initiating apoptosis [71]. Conversely, increased MFN1 and OPA1 levels promote mitochondrial fusion, increase oxygen consumption and ATP content, thus enhancing HCC proliferation [69]. Moreover, HCV infection reduces MFN2 levels and prompts the relocation of DRP1 to the mitochondria. This process triggers mitochondrial fission and mitophagy [72].

1.2.2 Abnormalities in mitochondria fission

Mitochondrial fission is driven by the recruitment of DRP1 to the MOM by other proteins such as mitochondrial fission 1 protein (FIS1) and mitochondrial fission factor (MFF) [73]. DRP1 binds to MOM proteins, including FIS1, MFF, MiD49, and MiD51, forming a ribbon-like structure, which tightens the mitochondrial fission site [74]. The breakdown of GTP in the MiD49/MiD51-DRP1-GTP complex causes the complex to contract and coil, leading to MOM contraction and mitochondrial fission [75]. In HCC, DRP1 triggers mitochondrial fission during G1/S transition of the cell cycle. This inhibits the p53 tumor suppressor protein by activating the ROS-dependent AKT/MDM2 (E3 ubiquitin protein ligase) pathway, subsequently increasing NF-κB activity [76]. This leads to the induction of Cyclin D1 and E1 expression, and promotes HCC cell proliferation [76]. Additionally, DRP1-mediated mitochondrial fission in HCC, results in the accumulation of mtDNA in the cytoplasm, stimulating the release of monocyte chemoattractant protein 1, which attracts tumor-associated macrophages (TAMs) and increases the polarization of M2-type TAMs, further promoting HCC cell proliferation [77]. High DRP1 mRNA and protein levels in metastatic HCC tissues reduce patient survival and promote intrahepatic lung metastasis.

HCC exacerbates mitochondrial fission under hypoxic conditions by overexpressing DRP1 and augmenting expression of the mitophagy-related protein B-cell lymphoma 2 (Bcl-2)-interacting protein 3 (BNIP3) [33]. DRP1-triggered mitochondrial fission regulates adhesion complexes through Ca2+/calmodulin-dependent protein kinase II, increasing ATP generation and subsequently increasing Ca2+ influx into mitochondria, which promotes HCC migration [78]. DRP1-mediated mitochondrial fission enhances ROS production, boosts NF-κB activity, inhibits TP53, enhances mitophagy, and suppresses apoptosis [79]. Additionally, DRP1-induced mitochondrial fragmentation increases caspase 3 levels in natural killer (NK) cells, thus promoting NK cell apoptosis and facilitating HCC immune escape [32]. Furthermore, post-translational modifications, including ubiquitination, SUMOylation, and phosphorylation, affect DRP1 recruitment to the OMM and GTPase activity [80]. The key phosphorylation sites include DRP1S600, which blocks mitochondrial fission, and DRP1S579, which is regulated by several kinases (cyclin-dependent kinase 1 [Cdk1/cyclin B], extracellular signal-regulated kinase [ERK1/2], protein kinase C δ [PKCδ], and Cdk5). These sites correspond to DRP1S643/ DRP1S637 and DRP1S622/ DRP1S616 in mouse and human DRP1 isoform 1, respectively [80]. DRP1S637 phosphorylation initiates mitochondrial fusion, expanding the number and size of mitochondrial cristae and increasing the assembly of OXPHOS complexes I-IV. This process also inhibits glycolysis through the NAD+/SIRT1 pathway, enabling HCC cells to survive under starvation conditions [81]. DRP1S600A knock-in mice display increased mitochondrial respiratory capacity across multiple tissues and enhanced whole-body lipid utilization as an energy source [80]. DRP1S616 phosphorylation promotes mitochondrial fission and lead to HCC proliferation, migration, invasion, and EMT [82]. Moreover, high-energy fructose palmitate upregulates FIS1 levels in HepG2 cells, induces steatosis, and triggers mitochondrial fission, leading to excessive ROS generation, dissipation of mitochondrial membrane potential, reduced OXPHOS activity, and increased caspase 3-mediated apoptosis [83]. An imbalance in mitochondrial dynamics can lead to mitochondrial failure and hepatocarcinogenesis.

1.3 Dysregulation of mitophagy induces hepatocarcinogenesis

Mitophagy is a selective form of autophagy which regulates mitochondrial levels to maintain energy metabolism [84]. Mitophagy removes damaged mitochondria through ubiquitination and recognition of cargo receptors. This process plays a key role in maintaining healthy liver function. Mitophagy involves the following stages [9]: mitochondrial fission, autophagosomes formation, and eventual fusion with lysosomes (shown in Fig. 2).

1.3.1 Mechanism of mitophagy

PINK1 is a maker of mitochondrial damage. When Parkin accumulates on the mitochondrial surface, it is drawn into the MOM [9, 84, 85]. Parkin amplifies this signal, whereas deubiquitinating enzymes regulate mitophagy by deubiquitinating either parkin or its mitochondrial targets. Relocation of Parkin increase, its E3 ubiquitin ligase activity [85]. This process promotes proteasomal degradation and leads to the formation of mitophagy-associated lysine (K) 48-linked and 63-linked polyubiquitin chains [86]. The degradation of substrates, such as Miro (Mitochondrial Rho GTPases) and MFN, mediated by K48-linked chains, inhibits mitochondrial dynamics and axonal transport. K63-linked chains are recognized by ubiquitin-binding adapters, such as p62/SQSTM1 and histone deacetylase 6 (HDAC6), which attach to damaged mitochondria and transport them to the isolation membrane through interactions with the autophagosome protein microtubule-associated protein 1 light chain 3 (LC3) [87]. This process is known as PINK1/Parkin-dependent mitophagy.

Another mechanism of mitophagy involves the binding of BNIP3, NIP3-like protein X (NIX), and FUN14 domain-containing protein 1 (FUNDC1) to LC3 to facilitate autophagosome formation [87]. BNIP3, similar to Bcl-2, has an LC3-binding motif and promotes mitophagy by linking with the LC3/GABARAP family of proteins [88]. NIX, a Bcl2-related MOM protein with a BH3 domain and an LC3 interaction region, recruits autophagy-related protein (ATG)32/ATG11 to autophagosome receptors. FUNDC1 is located in the MOM and is usually phosphorylated at Tyr18 and Ser13 by Src kinase and casein kinase 2 (CK2), respectively, which reduces its affinity for LC3. However, under hypoxic conditions or when the mitochondrial potential is lost, FUNDC1 is dephosphorylated by phosphoglycerate mutase/protein phosphatase. Subsequently, it binds to LC3 at the mitochondrial-endoplasmic reticulum junction through the LC3 interaction region sequence, to recruit DRP1 and promote mitophagy [87].

1.3.2 Mitophagy dysfunction causes carcinogenesis

Mitophagy helps HCC cells survive by clearing damaged hepatic mitochondria [89]. Through this process, HCC cells can adjust their metabolism to survive extreme conditions such as low nutrition or oxygen levels. In the tumor microenvironment, changes in mitophagy influence both inflammatory and immune responses. These changes help cancer cells escape immune detection by modifying immune cell activation and cytokine production [90]. HBV-related HCC regulates mitophagy through the PINK1/Parkin pathway, leading to DRP1 translocation and increased Parkin, PINK1, and LC3B expression. This process enhances mitophagy, inhibits the apoptosis pathway, and promotes hepatocarcinogenesis [91]. HBX results in the ubiquitination and degradation of MFN2 [91], leading to a poor prognosis for patients with HCC [92]. Thyroid hormone increases HBX ubiquitination in HBV-infected cells through PINK1/Parkin pathway, thereby enhancing mitophagy [93]. Early-stage MASCD triggers PINK1-Parkin-mediated mitophagy, which mice on high-fat/high-calorie diet counteracts hepatic lipid accumulation [94]. Mitophagy activation reduces hepatic steatosis in mice on high-fat diet and slows hepatocarcinogenesis of high-fat diet-mediated MASCD [55, 95]. Knock out of the serine/threonine protein kinase Mst 1, a cell survival regulator associated with liver regeneration, restores parkin-mediated mitophagy in mice, attenuates liver injury, and enhances hepatocyte viability [96]. Furthermore, SIRT3 overexpression enhances BNIP3-mediated, Parkin-dependent mitophagy. This process occurs through the ERK-cAMP response element-binding protein signaling pathway in mice on high-fat diet, which consequently inhibits hepatocyte apoptosis [97]. FUNDC1 also promotes mitophagy, reducing hepatocyte inflammation and the subsequent inflammatory response in mice on high-fat diet, which in turn inhibits hepatocarcinogenesis [98]. Consequently, mitophagy reduces oxidative stress by removing damaged hepatic mitochondria, which helps prevent hepatocyte damage and hepatocarcinogenesis. Enhancing SIRT3 activity could be used to treat nonalcoholic fatty liver disease [97].

1.4 Dysregulation of cell death influences hepatocarcinogenesis

In HCC, programmed cell death pathways trigger specific death cascades which dictate the development and progression of cancer. These pathways share common cytokines, indicating interactions between different types of cell death [99].

1.4.1 Necroptosis and pyroptosis

Necroptosis is a regulated form of programmed cell death driven by receptor-interacting protein kinase (RIPK) 3 and its downstream substrate, the mixed lineage kinase domain-like protein (MLKL) [100]. This process initiates with the autophosphorylation of RIPK1, which is activated by ROS (shown in Fig. 3). This activation recruits RIPK3, which promotes ROS generation [101]. RIPK3 phosphorylates MLKL, leading to the formation of oligomers which migrate to the cytoplasmic membrane to form selective pores [100]. This process allows the release of DAMPs such as HMGB1, interleukin 1α, and mtDNA. Similar to necrotic cells, pyroptotic cells display early plasma membrane permeabilization. Necroptosis-related microenvironmental factors influence the growth of intrahepatic cholangiocarcinomas in oncogenically transformed mouse hepatocytes [102]. However, mouse hepatocytes surrounded by apoptotic hepatocytes, driven by the same oncogenes, can also lead to HCC [102]. Necroptosis is associated with hepatocarcinogenesis and metastasis in patients with HCC [103]. It also contributes to immune cell infiltration and is involved in patient with HCC survival outcomes [103]. An increase in mitochondrial GSH levels in HepG2 cells protects cytochrome C and inhibits necroptosis via the c-Jun N-terminal kinases pathway [104]. In HepG2 cells with low levels of S-nitroso glutathione reductase (GSNOR, an enzyme in alcohol dehydrogenase), the activity of OXPHOS complex II is inhibited. This leads to necroptosis via the PARP1/RIPK1 pathway, thereby inhibiting tumor growth [105]. Necroptosis plays a paradoxical role in liver pathology; while it promotes inflammation, fibrosis, and HCC development, it can also trigger tumor cell death in existing HCC and fight tumors by altering the necrotic tumor microenvironment [99].

Fig. 3
figure 3

Molecular mechanisms of necroptosis/pyroptosis in HCC. Binding of tumor necrosis factor (TNF) to its receptor initiates both necroptosis and apoptosis. In collaboration with receptor-interacting protein kinase 1 (RIPK1), Fas-associated death domain (FADD), and TNFR1-associated death domain protein (TRADD)/ receptor-interacting protein kinase 3 (RIPK3), caspase 8 triggers apoptosis. However, if Casp 8 inhibition promotes mixed lineage kinase domain-like pseudokinase (MLKL), RIPK1, and RIPK3 expression, leading to necrosome formation. Viral infections and mitochondrial damage can activate the Z-DNA Binding Protein 1 (ZBP1)-RIPK3 pathway, resulting in necrosome formation. Once phosphorylated, MLKL creates membrane pores which facilitate the release of specific damage-associated molecular pattern (DAMPs) molecules. Simultaneously, the accumulation of extracellular sodium ion (Na+) and calcium ion (Ca2+) in the cytoplasm leads to cell swelling and cell membrane rupture. DAMPs trigger pyroptosis through pattern recognition receptor (PRR). The NOD-like receptor family pyrin domain containing 3 (NLRP3) receptors, along with NIMA-related kinase 7 (NEK7), apoptosis associated dot like protein (ASC), and Pro-casp 1, forms the NLRP3 inflammasome. The inflammasome then triggers Casp-1, which promotes Gasdermin D (GSDMD) cleavage. Casp-4/5 activation leads to GSDMD cleavage. The N-terminal fragment of GSDMD forms a membrane pore, leading to the release of cytoplasmic contents, electrolytes, and specific cytokines such as interleukin (IL) 1α, IL-1β, IL-18, and leukotriene B4 (LTB4). Concurrently, potassium ion (K+) in the cytoplasm is expelled from the cells. ATP, adenosine triphosphate; C, C terminal; Casp4/5, caspase 4/5; Casp8, caspase 8; cIAP1/2, cellular inhibitor of apoptosis protein 1/2; HMGB1, high mobility group box 1; LPS, lipopolysaccharide; mtDNA, mitochondrial DNA; N, N terminal; P, phosphate group; PAMPs, pathogen-associated molecular pattern; ROS, reactive oxygen species; TNFR, tumor necrosis factor receptor; TRAF2, TNF receptor-associated factor 2; TRAF5, TNF receptor-associated factor 5. The arrow symbolizes promotion, while the blunt line represents inhibition. Black arrows indicate the entry and exit directions across the cell membrane

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Pyroptosis (Fig. 3) can initiate through the following two pathways in response to an immune trigger from a DAMP: the caspase-1-dependent classical inflammasome pathway and caspase-4/5-activated non-classical inflammasome pathway [106]. This process involves DNA fragmentation, chromatin condensation, and activation of caspases 3 and 7 [107]. Pyroptosis-associated poly (ADP-ribose) polymerase cleavage occurs through the activation of NLR family pyrin domain 3 (NLRP3) and NLR family caspase activation and recruitment domain 4 inflammasomes [106]. Granzymes typically induce apoptosis by activating caspase-3 or its substrates [108]. However, caspase-3 activation can cause pyroptosis by cleaving Gasdermin E (GSDME) [109]. Notably, granzymes produced by NK cells can trigger pyroptosis in cancer cells, independent of caspases [109]. In addition, caspase-1 levels in human HCC tumor are lower than those in normal paracancerous tissues, and loss of caspase-1 expression is involved in the HCC pathogenesis [110, 111]. Thus, NLRP3 inflammasome inhibition triggers pyroptosis by activating caspase-1 in patients with HCC [112]. However, excessive ROS generation activates the inflammasome, which leads to the pyroptosis of HCC cells by binding of the NLRP3 inflammasome [112]. Under hypoxic conditions, HBx induces hepatocyte pyroptosis by activating the NLRP3 inflammasome [103]. Thus, pyroptosis and its associated molecules can both promote and inhibit tumor growth.

1.4.2 Ferroptosis and cuproptosis

Ferroptosis is characterized by unregulated lipid peroxidation and redox imbalance (shown in Fig. 4). Inhibition of the amino acid transport system, known as the cystine/glutamate antiporter (System Xc−), and the selenoenzyme GPX4 result in decreased GSH synthesis [113]. ROS exceed the antioxidant capacity of cells, and oxidative stress can directly or indirectly damage macromolecules such as proteins, nucleic acids, and lipids. This damage initiates the release of lipid peroxides from mitochondria, leading to ferroptosis [114]. SRY-Box transcription factors (SOX) act as both tumor promoters and suppressors in HCC by modulating key signaling pathways. These pathways include Wnt/β-catenin, TGFβ, Notch, AMP-activated protein kinase (AMPK)/mTOR, and p53 signaling, which can be affected through transcription-dependent or independent mechanisms [115]. SOX8 inhibits de novo lipogenesis, glycolysis, the tricarboxylic acid cycle, and the pentose phosphate pathway, leading to increased mitochondrial oxidative stress and lipid peroxidation in HCC cells [116]. Excessive SOX8 can modify mitochondrial structure and negatively affect OXPHOS function, and improve survival rates in patients with HCC by triggering cancer cell ferroptosis [116]. SOX8 influences glycolipid and Fe2+ metabolism in HCC cells, leading to ferroptosis by enhancing the expression of related genes and increasing intracellular Fe2+ levels [117]. Mitochondrial translocator protein increases antioxidant gene and programmed death ligand 1 (PD-L1) expression through the p62/KEAP1/Nrf2 pathway, providing resistance to ferroptosis and suppressing anti-tumor immunity in HCC cells [118]. In addition, activating ferroptosis signaling may trigger tumor cells to develop tolerance to endoplasmic reticulum stress, thus preventing endoplasmic reticulum stress-induced cell death [99]. Collectively, ferroptosis plays a vital role in anti-tumor activity.

Fig. 4
figure 4

Molecular mechanisms of ferroptosis/cuproptosis in HCC. An influx of cysteine into tumor cells can lead to accumulation of the cysteine-glutathione (GSH)-glutathione peroxidase 4 (GPX4) axis. Ferroptosis is triggered by the synthesis and peroxidation of polyunsaturated fatty acid-containing phospholipids (PUFA-PLs), iron metabolism, and mitochondrial metabolism. The defense system against ferroptosis mainly comprises the GSH, ferroptosis suppressor protein-1 (FSP1)-ubiquinol (reduced form of coenzyme Q10, CoQ10H2), dihydroorotate dehydrogenase (DHODH)-CoQ10H2, and GTP cyclohydrolase-1 (GCH1)-tetrahydrobiopterin (BH4) systems. A decrease in intracellular GSH levels or GPX4 activity can lead to the excessive accumulation of intracellular lipid reactive oxygen species (ROS) and lipid peroxidation. Iron initiates a non-enzymatic Fenton reaction and serves as a cofactor for arachidonic acid lipoxygenase (ALOX) and cytochrome P450 oxidoreductase (POR). It promotes lipid peroxidation and mitochondrial metabolism and enhances ROS, adenosine triphosphate (ATP), and PUFA-PL. FSP1 prevents iron-induced apoptosis through NAD(P)-H-catalyzed Co-enzyme Q10 (CoQ10) regeneration. FIN56 induces iron toxicity by enhancing GPX4 degradation and reducing CoQ10 levels. If ferroptosis promotion substantially exceed the detoxification capacity of the ferroptotic defense system, lethal accumulation of lipid peroxides on the cell membrane can cause membrane rupture and ferroptotic cell death. Oxidative damage to mitochondrial membranes impairs enzyme function in the tricarboxylic acid (TCA) cycle, leading to carboxy proptosis. The key factors in Cu-ionophore-induced cell death are Ferredoxin 1 (FDX1) and protein-lipid sequestration. Excessive Cu can cause aggregation and loss of function of lipid-sequestering proteins, resulting in the instability of Fe-S cluster proteins. FDX1 reduces Copper II (Cu2+) to Copper I (Cu+), whereas GSH prevents cuproptosis. The presence of Cu+ promotes lipid acylation and enzyme aggregation, particularly in enzymes involved in regulating the mitochondrial TCA cycle, such as dihydrolipoamide S-Acetyltransferase (DLAT). This, along with the instability of Fe-S cluster proteins, damages the mitochondrial membrane and TCA cycle, leading to Cu-induced apoptosis. ATPase Cu transporting beta (ATP7B) also regulates Cu-ion accumulation by mediating Cu-ion entry and exocytosis. α-KG, α-ketoglutaric acid; Cys, Cysteine; Fe2+, ferrous iron; Gln, Glutamine; Glu, Glutamate; GSSG, Glutathione disulfide; LA, ipoylation; LAT, dihydrolipoamide S-acetyltransferase; LIAS, lipoyl synthase; PUFA, polyunsaturated fatty acid-containing; SLC3A2, solute carrier family 3 member 2; SLC31A1, solute carrier family 31 member 1; SLC7A11, solute carrier family 7 member 11; STEAP, 6-transmembrane epithelial antigen of prostate; TFRC, transferrin receptor protein 1

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Cuproptosis is triggered by Cu I (Cu+) toxicity [119], primarily through excessive Cu+ exposure and subsequent proteotoxicity (shown in Fig. 4). Cu+ serves as a cofactor for the components of mitochondrial respiration and ATP generation, specifically for OXPHOS complexes III and IV and cytochrome C oxidase subunits I (MT-CO1) and II (MT-CO2) [120]. However, Cu+ accumulation can disrupt proteasome function, hinder protein degradation, and lead to the accumulation of misfolded proteins [121]. Additionally, Cu+ can replace zinc in p53 tumor suppressor proteins, leading to protein misfolding and the loss of tumor suppressor activity [119]. High Cu+ concentrations increase toxicity by triggering various forms of cell death; including apoptosis, paraptosis, pyroptosis, ferroptosis, and cuproptosis [119, 122]. Excessive Cu+ accumulation aids in assembly of the autophagy machinery that plays a dual role in regulating whether cells survive or die under stress and promotes carcinogenesis, growth, and proliferation of cancer cells [119, 122]. An increase in serum Cu+ concentration in patients with HCC also amplifies the expression of the proto-oncogene MYC, thereby promoting HCC cells proliferation, growth, and metastasis [123]. High Cu+ concentrations enhance expression of the immune checkpoint protein, PD-L1. This is achieved by strengthening STAT3-dependent transcription and inhibiting the UPS-mediated degradation of PD-L1, thereby weakening anti-tumor immunity [124]. Interferon can stimulate PD-L1 expression in macrophages through a STAT3-dependent mechanism. This inhibits CD8+-T cell function, which can accelerate tumor growth and predict poor survival rates in patients with HCC [125]. Patients with ATP7B mutations are more susceptible to HCC due to abnormal Cu+ accumulation in the liver [126]. Genetic defects in ATP7B may lead to the chronic elevation of liver Cu+ levels. This promotes HCC development of by upregulating cell cycle genes such as Cdc2, Ccnd1, and Ccne1 [127].

The relationship between cuproptosis and ferroptosis is complex [119]. Cu+ serves as a cofactor for iron-metabolizing enzymes; its absence can lead to ferrous iron (Fe2+) deficiency. This deficiency hinders the absorption of hepatic mitochondrial Fe2+, and reduces heme synthesis. Cu+ ionophores increase cellular and mitochondrial Fe2+ levels, leading to oxidative stress and ferroptosis [119, 128, 129]. Moreover, exogenous Cu+ promotes cancer cell ferroptosis by initiating autophagic GPX4 degradation [130]. GSH, a cofactor of GPX4 and Cu+ chelator, is involved in a feedback loop which links Cu+-induced apoptosis to ferroptosis [131]. Additionally, the Cu+ ionophore, disulfiram, initiates the degradation of Cu+-transporting ATPase 1 (ATP7A) in cancer cells through the UPS. This results in the accumulation of Cu+, subsequent generation of ROS, and ultimately, ferroptosis [132].

1.5 Mitochondrial biogenesis disorders induce hepatocarcinogenesis

Cells initiate mitochondrial biogenesis in response to stress triggered by energy demands. This process involves transcription factors, such as nuclear respiratory factor (NRF) 1 and NRF2. It also includes peroxisome proliferator-activated receptor γ coactivators (PGC) 1-α and PGC-1β, which guide mitochondrial biosynthesis in conjunction with coactivators [17, 133]. Low PGC1α levels predict poor prognosis in patients with HCC [134]. The AMPK enhances this process by activating PGC-1α [17, 133]. PGC-1α, a critical regulator of energy homeostasis, facilitates the export of mRNA from the nucleus and regulates liver metabolism at the transcriptional level [133, 135]. Its functions include OXPHOS, gluconeogenesis, and fatty acid synthesis. PGC-1α enhances oxygen consumption, oxidative phosphorylation, and mitochondrial biogenesis in cancer cells. It also promotes hepatocarcinogenesis by improving mitochondrial and fatty acid metabolism [136]. Under hypoxic conditions, HCC cell promotes mitochondrial biogenesis and proliferation by increasing the expression of PGC-1α [137]. SIRT1 participates in NAD-dependent deacetylase/PGC-1α signaling and contributes to HCC cell metastasis [138]. Furthermore, HCC metastasis can be prevented by regulating the WNT/β-catenin/pyruvate dehydrogenase kinase (PDK) 1 pathway and aerobic glycolysis via PGC-1α inhibition [134]. The p53 pathway inhibits mitochondrial biogenesis and OXPHOS activity, which subsequently decelerates cancer cell proliferation by reducing PGC-1α expression [139].

NRF1 was overexpressed and hyperactive in HCC tissue, and elevated NRF1 levels indicated poor prognosis for patients with HCC [140]. Higher NRF2 expression was found only in younger patients with HCC, but showed no statistically significant impact on long-term survival [141]. NRF1 and NRF2 activate the mitochondrial transcription factor A (TFAM) and bind to the promoter region of nuclear genes which encode the five OXPHOS complex subunits. This binding increases the respiratory complex assembly and regulates three processes: heme biosynthesis, transcription of nuclear genes encoding mitochondrial proteins, and mtDNA replication and transcription [142]. TFAM is a mitochondrial protein encoded by nuclear genes and is transported from the cytoplasm to mitochondria. Through TFAM post-translational modifications which regulate mitochondrial rRNA supply, these proteins may control the global regulation of OXPHOS biogenesis [143]. Furthermore, TFAM binds to mtDNA, playing an essential role in DNA replication and maintaining normal mitochondrial function [143, 144]. TFAM deficiency blocks the TCA cycle and increases malonyl-CoA levels within cells, promoting the proliferation of HCC in mice [145]. Hepatocytes constantly struggle to maintain cellular balance due to the liver physiological functions including the maintenance of mitochondrial function. NRF1, NRF2, and TFAM are indispensable for maintaining mitochondrial homeostasis, which abnormal expression disrupts mitochondrial function.

1.6 Mitochondria-associated chemoresistance during HCC treatment

The reasons for the highly refractory nature of HCC to classical chemotherapy remain unclear. HCC often exhibits increased mitochondrial biogenesis to meet high energy demands, contributing to resistance against chemotherapeutic drugs which target cellular metabolism or induce oxidative stress [146, 147].

1.6.1 Chemoresistance associated with mitochondrial failure

Some chemotherapeutic drugs produce anti-tumor effects by triggering excessive ROS generation. However, HCC upregulates antioxidant defense mechanisms to counteract the ROS-mediated cytotoxic effects of chemotherapeutic drugs [28,29,30]. Tigecycline reduces the chemoresistance of HCC to cisplatin by inhibiting the OXPHOS complex and enhancing mitochondrial oxidative stress [148]. HCC induces chemoresistance and apoptosis by regulating the mitochondrial pathway [149]. HCC can escape cell death signals by upregulating anti-apoptotic proteins or altering the mitochondrial membrane potential [149]. The mitochondria of HCC contain high levels of B-cell lymphoma-extra-large and myeloid cell leukemia-1, promoting HCC response to regorafenib and developing resistance to sorafenib [150, 151].

Dichloroacetate inhibits PDK4 (pyruvate dehydrogenase lipoamide kinase isozyme 4) and can reverse the chemoresistance of HCC cells to sorafenib or cisplatin [152]. Furthermore, the mitochondrial transcription factor TFAM, which is essential for mtDNA transcription, is linked to metabolic changes in tumorigenesis and chemoresistance. TFAM depletion counteracts HCC resistance to doxorubicin and sorafenib through AMPK activation and mitochondrial dysfunction [153]. Thus, HCC affects the efficacy of chemotherapeutic drugs by altering mitochondrial function.

1.6.2 Mitophagy-related chemoresistance

Mitophagy maintains cell health by removing damaged mitochondria and reducing harmful oxidants. This process affects cancer development through metabolism, stemness, and the tumor environment, helping cells survive stress from treatments [154]. Downregulation of the denitrosylating enzyme, GSNOR, in HCC cell causes mitochondrial changes, making tumors sensitive to toxins such as α-tocopheryl succinate (αTOS). GSNOR-deficient HCC cell shows defective mitophagy, increasing αTOS toxicity. Parkin depletion further boosts of αTOS by inhibiting mitophagy [155]. The increased sensitivity of HCC cells to melatonin-induced sorafenib is associated with ROS production and mitophagy [156]. Stepholidine hydrochloride enhances mitochondrial fission and mitophagy via the AMPK pathway, thereby increasing chemoresistance of HCC cells [157]. Blocking mitophagy with 3-methyladenine can aid in reducing mice tumor size, improving the anti-tumor activity of stepholidine salts, and impeding chemoresistance [157]. Thus, mitophagy dysregulation in HCC cells can lead to chemoresistance. Cancer cells utilize mitophagy to remove damaged mitochondria, reduce cytotoxicity, and promote cell survival.

1.6.3 Chemoresistance related to pyroptosis, and ferroptosis

Ferroptosis involves the build-up lipid peroxides, which damages membranes and leads to cell death. GPX4 is crucial in protecting cells from lipid peroxidation. HCC often increases the levels of GPX4 or other antioxidants to resist chemotherapy-induced oxidative stress and promote chemoresistance. Sorafenib increases the levels of lipid peroxidation markers, malondialdehyde production, and GSH consumption by inhibiting HBx-interacting proteins in HCC cells, thus promoting ferroptosis and cell death [158]. Chemotherapy-activated epidermal growth factor receptor signaling transfers lysyl oxidase-like 3 to the mitochondria, enhancing its activity via S704 phosphorylation by adenylate kinase 2. It stabilizes dihydroorotate dehydrogenase (DHODH), thus inhibiting chemotherapy-induced ferroptosis. Combining low-dose oxaliplatin with the DHODH inhibitor leflunomide effectively inhibits HCC in mouse model, induces ferroptosis, improves chemotherapy sensitivity, and reduces toxicity [159].

Thus, pyroptosis may influence chemoresistance in HCC. It is involved in inflammasome and caspase activation, and cause cell swelling and membrane rupture. Sorafenib induces macrophage pyroptosis via caspase 1 and amplifies NK cell-mediated cytotoxicity in HCC mouse model [160]. Euxanthone, a naturally occurring xanthonoid, triggers pyroptosis in a caspase-2-dependent manner, leading to HCC cell death and inhibition of proliferation and invasion [111]. Miltirone, an active constituent of a traditional Chinese herbal medicine Salvia miltiorrhiza Bunge, stimulated HCC cells-dependent pyroptosis through the ROS/ERK 1/2-BAX-caspase 9-caspase 3-GSDME pathway [161]. Miltirone significantly inhibited tumor growth and induced cell death through pyroptosis in HCC model-mice [161]. Curcumin affects the progression of pyroptosis in HCC cells via ROS and GSDME [162]. Alpine isoflavones induce autophagy in HCC cells, trigger pyroptosis through the NLRP3 inflammasome, and inhibit HCC cell growth and metastasis [163]. Estrogen triggers the NLRP3 inflammasome through the estrogen/estrogen receptor-β/AMPK/mTOR pathway, decelerating the occurrence of HCC cells and inducing pyroptosis [164]. Thus, triggering ferroptosis and pyroptosis improves the efficacy of chemotherapy and reduces toxicity while inhibiting the growth and metastasis of liver cancer cells.

2 Conclusion

The unique tumor microenvironment of HCC affects mitochondrial function. Irregularities in GSH and GPX levels, increased expression of HMGB1, RHOT1, or RAC1, and loss of SIRT3 can lead to oxidative stress and excessive ROS generation. Alternatively, failure of mtUPR may cause mitochondrial dysfunction or disorganization, eventually releasing DAMPs. Loss of MFN1 and OPA1 impedes mitochondrial fusion in HCC, whereas increased fission induced by DRP1 enhances glycolysis, inhibits OXPHOS, and promotes HCC growth. The PINK1/Parkin pathway regulate mitophagy, inhibits apoptosis, and supports hepatocarcinogenesis. Several new types of cell death, including necroptosis, pyroptosis, ferroptosis, and cuproptosis, significantly affect the onset, recurrence, and hepatocarcinogenesis of HCC. They also play critical roles in chemoresistance. Although no specific HCC treatment using mitochondrial therapy currently exists, preventing mitochondrial dysfunction and managing the related mechanisms could serve as promising new treatment strategy. Specifically, regulating mitochondrial function, dynamics, and related cell death processes may help overcome chemoresistance and benefit more patients with HCC. Thus, the findings summarized in this review may help guide future research focused on improving patient outcomes using innovative therapies.