The Curative and Preventative Effects of Traditional Chinese Medicine on Ferroptosis of Hepatocellular Carcinoma

Abstract

Primary hepatocellular carcinoma (HCC), a leading variant of primary liver cancer, holds significant global prevalence with strong implications for morbidity, mortality, and prognosis. Prevention and treatment paradigms are perpetually evolving in response to this malignancy. Ferroptosis, an iron and reactive oxygen species (ROS) dependant mode of cellular death, is catalyzed by an overabundance of lipid peroxidation, subsequently causing plasma membrane rupture. There is a unique interest in the relationship of ferroptosis with HCC development and progression, as compared to the interplay of apoptosis, autophagy, and necroptosis. Recent discoveries underscore the implications of ferroptosis in HCC evolution. Moreover, Traditional Chinese Medicine (TCM) and its respective active components display anti-HCC properties, a mechanism thought to be primarily attributed to the induction of ferroptosis in HCC cells. In support of preventive and therapeutic strategies for HCC, this manuscript provides a comprehensive review of the role of ferroptosis in HCC, its regulatory network, and the cutting-edge research focused on the treatment of HCC via ferroptosis modulation using TCM.

Introduction

Hepatocellular carcinoma (HCC), a malignant tumor originating from hepatocytes or biliary epithelial cells, is currently the third highest cause of global cancer-related deaths. Projections suggest that this type of cancer could exceed 1 million cases by 2025.^1,2 Identified as the sixth most common cancer globally, HCC poses a significant threat to humankind and its overall vitality. As the paramount subtype of liver cancer, HCC accounts for an astounding 75% to 90% of all primary liver malignancies, casting a grim foreboding on patient prognosis. ³ Notably, it is noteworthy to mention that HCC exhibits a higher incidence in males compared to females. ⁴ Regrettably, the overall 5-year survival rate is less than 15%, with late-stage patients observing a precipitous dip to a mere 10.1%.^5,6 The main etiological factors in HCC's development include chronic infections caused by Hepatitis B or C, sustained and extensive alcohol intake, nonalcoholic fatty liver disease resulting from obesity, and diabetes. Alarmingly, metabolism-related HCC is on a rapid upward trajectory in developed countries. ⁷

Ferroptosis, a form of cell death that is strictly regulated, relies heavily on iron and reactive oxygen species (ROS). ⁸ Iron, an indispensable micronutrient, assumes a central function in myriad biological phenomena, attributable to its propensity for electron donation and acceptance. ⁹ These encompass integral metabolic activities such as cellular respiration, DNA replication, and detoxification pathways. Nevertheless, its overabundance portends potential harm. Deviations in iron regulatory mechanisms are inextricably intertwined with the pathobiology of HCC.^10,11 Superfluous iron can instigate the production of destructive ROS through the Fenton reaction, inciting oxidative stress and DNA impairment. ¹² This might perpetrate mutations, sparking malignant metamorphosis. Additionally, the amplification of malignant entities necessitates a robust iron presence, rendering iron overwhelm a probable HCC risk determinant. Iron, therefore, operates as an accelerant in the precursory phases of hepatic malignancy, and a propellant in HCC metastasis. ¹³ Ferroptosis is caused by an excessive accumulation of iron ions and an increase in lipid peroxidation, ultimately leading to significant rupture of the plasma membrane. Importantly, ferroptosis is closely linked to the onset and progression of HCC, distinguishing it from apoptosis, autophagy, and necroptosis in this context. ¹⁴ When scrutinizing the ultrastructure during ferroptosis, a series of characteristic transformations can be seen. The outer mitochondrial membrane undergoes rupture, and the cell membrane experiences fragmentation and displays bleb formation. The cell morphology shifts towards a spherical shape, accompanied by noticeable shrinkage in mitochondrial size. Concurrently, there is an increase in density in the bilayer membrane. Additionally, the cristae structures within the mitochondria are either reduced or disappear completely during this fascinating process. ¹⁵ It's noteworthy that despite these structural changes, the morphology of the nucleus remains relatively intact, with no clear signs of chromatin condensation.

To pave the way for new research in the purview of HCC treatment via TCM, this review delves deep into the intricacies of ferroptosis, shedding light on its mechanistic foundations and the complex regulatory networks incorporated. Furthermore, it scrutinizes the cardinal function of lipid metabolism reprograming in driving ferroptosis and ponders over prospective therapeutic strategies targeting ferroptosis within the framework of HCC management.

Mechanism and Regulatory Network of Ferroptosis in HCC

Ferroptosis, typifying a nascent archetype of programmed cellular decease, is instigated by the complex interplay of lipid peroxidation, multifarious antioxidant pathways that hinge upon glutathione, and the elaborate choreography of iron metabolism. The unique mechanisms of ferroptosis play a crucial role in a broad spectrum of cancers, and it is characterized by an iron-dependent form of regulated cell death that is induced by the insurmountable buildup of lipid peroxidation products, the depletion of plasma membrane polyunsaturated fatty acids, and the inactivation of the system Xc⁻–GSH–GPX4 pathway. In contrast, tumor cells have a robust antioxidant defense system, including various pathways that are glutathione-dependent and those that are not dependent on glutathione. These can effectively reduce or prevent the process of lipid peroxidation. Therefore, tumor cells usually have better resistance to ferroptosis. In the context of HCC, ferroptosis can be triggered by several pathways distinct from other types of cancer due to the unique metabolic characteristics of liver cells and their exposure to iron. The abundance of iron and lipid in liver cells, coupled with the unique metabolic processes that occur within these cells, can amplify the effects of ferroptosis inducers and make HCC cells more susceptible to ferroptosis. Further, HCC cells have unique genetic and molecular landscapes, which could lead to a distinct response to ferroptosis. For instance, some specific mutations or gene expressions in HCC might affect the sensitivity of ferroptosis.

Within the ambit of HCC, ferroptosis assumes a unique morphology—referred to as HCC ferroptosis. Especially, the CISD1 protein mitigates the accumulation of intramitochondrial Fe²⁺ and ROS within HCC cells, thereby impeding the initiation of ferroptosis. ¹⁶ Sorafenib, a protein kinase inhibitor utilized for HCC treatment, hampers the transport functionality of System Xc-, decreases intracellular GSH reserves, and thereby accelerates ferroptosis in HCC cells. Additionally, Haloperidol amplifies the aggregation of Fe²⁺ and accrual of ROS within HCC, boosting the impact of both sorafenib and erastin, and catalyzing the onset of ferroptosis within HCC. ¹⁷ The subsequent segment endeavors to furnish an exhaustive scrutiny of the operative mechanisms and controlling networks underpinning ferroptosis in HCC. This exploration will be tackled from a tripartite vantage point, underscoring the interaction of these constituent components, as explicated in Figure 1.

Figure 1.

Mechanism and regulatory network of ferroptosis in HCC. The antioxidant pathway (including both GSH-dependent and GSH-independent antioxidant pathways) helps control lipid peroxidation, thus inhibiting ferroptosis. GSH, a critical antioxidant within cells, performs an essential role in this procedure. Its synthesis is reliant on cysteine, which is transported into cells by system Xc⁻. After GSH is synthesized, it can then be oxidized by GPX4 to regulate the levels of lipid peroxides in the cell. Any disruption in GSH levels leads to an increase in lipid peroxides and the subsequent induction of ferroptosis. Additionally, the interaction between CoQ10-AIFM2 aids in suppressing the lipid peroxidation process. Lipid peroxidation, facilitated by enzymes like ACSL4 and LPCAT3, essentially impacts the generation of lipid peroxides, which further escalates ferroptosis. Key enzymes (for instance, ACSL4 and LPCAT3) convert specific acids (for instance, PUFAs) into forms that can be incorporated into cellular membranes. The oxidation of these products by LOX subsequently yields lipid peroxides. Iron metabolism supports the balanced sequestration and release of iron in cells. The iron transportation and reduction mechanism involves various proteins like transferrin, TFR1, and STEAP3, with DMT1 ultimately releasing the iron into the cytoplasm. The iron can be securely stored in ferritin without contributing to ROS production. On the other hand, excessive accumulation of iron facilitates ROS production through the Fenton reaction mechanism, thereby stimulating ferroptosis.

Antioxidant Pathways of Ferroptosis in HCC

GSH-Dependent Antioxidant Pathway

The critical orchestrator of ferroptosis regulation in HCC resides in the complex System Xc⁻–GSH–GPX4 antioxidant pathway. ¹⁸ The fundamental constituents of the System Xc⁻, SLC3A2, and SLC7A11 operate in synergy to regulate the precise exchange of extracellular cystine and intracellular glutamate, thereby maintaining an optimal 1:1 ratio.^19–21 SLC7A11, a multipass transmembrane protein, serves to mediate the antiporter activity of cystine/glutamate in the System Xc⁻. In contrast, SLC3A2, a single-pass transmembrane protein, functions as a chaperone that facilitates the stabilization of SLC7A11 protein, hence ensuring its accurate membrane localization. Moreover, they enable the conversion of cystine to cysteine, facilitating its cellular uptake. ²² GSH, a vital redox mediator of the cellular microenvironment, comprises glutamate, cysteine, and glycine. GSH exists in 2 interchangeable states: the reduced form, depicted as GSH, and the oxidized form, notated as GSSG. The interconversion between these states was effected by the combined enzymatic activity of GPX4 and GSR. During this complex biochemical procedure, GSH transitions from a reduced to an oxidized state, forming GSSG, after which it is catalytically restored to its reduced form through the agency of GSR. ²³ GSH assumes a pivotal role in preserving the intricate balance of intracellular redox homeostasis. ²⁴ Subsequently, any depletion of GSH obstructs the GPX4-catalyzed antioxidant defenses, accruing lipid ROS levels within the cellular microenvironment. These cumulative impacts eventually lead to the compromise of cell membrane integrity, garnering adverse cellular outcomes.

GSH-Independent Antioxidant Pathways

Distinct from GSH-dependent mechanisms, various GSH-independent systems employ diverse strategies to shield themselves against the ravages of ferroptosis. CoQ10, a byproduct generated within the mevalonate pathway, assumes a pivotal role in the mitochondrial electron transport chain. Furthermore, CoQ10 exhibits remarkable antioxidant properties, extending its protective mantle over both mitochondria and cell membranes. ²⁵ Beyond its role as a pro-apoptotic factor within mitochondria, AIFM2 serves as an oxidoreductase at the cell membrane. In this capacity, it catalyzes the conversion of CoQ10 to its reduced form, CoQ10–panthenol. This reduced form, CoQ10–panthenol, exerts its protective influence by effectively sequestering free radicals, thereby thwarting the pernicious process of lipid peroxidation. ²⁶ The myristoylation of AIFM2 serves as a pivotal modulator, effecting the transition from a pro-apoptotic to an anti-ferroptotic function. In addition to this myristoylation-driven switch, AIFM2 employs another stratagem to impede ferroptosis at the cell membrane. It activates the ESCRT-III pathway, thereby instigating the repair of the cell membrane, further fortifying the cell against the pernicious effects of ferroptosis. ²⁷ These findings underscore that CoQ10 synthesis within multiple organelles possesses the capacity to thwart the onset of ferroptosis. Nevertheless, it remains an open question whether this defensive mechanism is exclusive to tumors or exhibits a broader applicability across various cellular contexts.

Lipid Peroxidation of Ferroptosis in HCC

The escalation of intracellular lipid peroxidation, a phenomenon that leads to oxidative impairment of cell membranes and culminates in cellular demise, stands as the prevalent biochemical hallmark of ferroptosis. PUFA characterized by their numerous double bonds, are the principal wellspring of lipid peroxidation. Their susceptibility to rapid deterioration at the hands of ROS renders them a primary target in this oxidative cascade. ²⁸ Certain enzymes in the lipid metabolism pathway serve as potent facilitators of ferroptosis, actively promoting the conversion of PUFAs into PUFA-CoA. ACSL4 plays a pivotal role in this process by activating PUFAs. ²⁹ Following the ACSL4-mediated esterification process, LPCAT3 then enters the scene, catalyzing the attachment of PUFAs to phospholipids, thereby PUFA-PL. ³⁰ In consonance with related research, the enzyme LOXs plays a significant role by catalyzing the direct oxidation of phospholipids rich in PUFAs-PL. This enzymatic activity represents a crucial regulatory mechanism in the context of ferroptosis. ³¹ LOX inhibitors have demonstrated efficacy in thwarting ferroptosis induced by both erastin and the ferroptosis activator RSL3. It's worth noting that while LOXs play a significant role in lipid peroxidation during ferroptosis, other enzymes such as NADPH oxidase and cytochrome P450 oxidoreductase are also implicated in this intricate process, ³² it is unclear how these enzymes potentially impact ferroptosis in HCC.

Iron Metabolism of Ferroptosis in HCC

The majority of intracellular iron exists either in the form of free Fe²⁺ ions or is stored as Fe³⁺ within ferritin. ³³ Via the Fenton reaction, the presence of Fe²⁺ catalyzes the reaction with H₂O₂, yielding hydroxyl radicals that are capable of inflicting damage upon PUFAs within cell membranes. Ferritin, as the primary iron storage protein, plays a pivotal role in preventing the oxidation of Fe²⁺ by H₂O₂. However, it's noteworthy that in various cell cultures, including HCC cells, ferritin exhibits a dual role. In addition to its iron-sequestering function, ferritin also promotes ferroptosis through a selective autophagy process known as ferritinophagy. ³⁴ Indeed, an array of intricate cellular mechanisms governing iron acquisition, storage, utilization, and export can significantly influence a cell's susceptibility to ferroptosis. Nevertheless, the broader impact of systemic iron metabolism, encompassing factors such as iron intake and tissue distribution, on the regulation of ferroptosis remains a subject of uncertainty and requires further investigation.

TCM Intervention for Ferroptosis in HCC

In the realm of TCM, HCC is classified under several categories, including “hepatoma,” “accumulation,” and “Zheng Gan.” These classifications within TCM represent different perspectives and approaches to understanding and managing the condition based on traditional Chinese medical principles. ³⁵ HCC is indeed characterized by a multifaceted etiology, diverse pathogenesis, and a wide range of symptoms and manifestations. In the realm of TCM, the approach to treating HCC typically revolves around principles that include minimizing adverse reactions, bolstering the patient's immune response, improving their overall quality of life, and extending their survival time. This holistic approach aims to address the complex nature of the condition and enhance the overall well-being of the patient while managing the disease. ³⁶ TCM provides distinct advantages in both the early intervention and comprehensive management of HCC. TCM principles, including the “overall concept” and “syndrome identification and treatment,” are well-suited to address the specific needs of HCC patients. In the context of HCC pathogenesis, which involves the interplay of “cancer toxins causing deficiency and toxic deficiency feedback,” TCM emphasizes an approach centered around “invigorating qi, removing blood stasis, and detoxicating methods” as a key focus. Additionally, TCM theory, incorporating the concept of “survival with tumor,” forms the foundation of treatment strategies. TCM interventions, which encompass detoxification, pathogen elimination, and deficiency tonification, hold the potential to significantly enhance the clinical outcomes and survival benefits for patients grappling with HCC. This holistic approach aims to address not only the tumor itself but also the overall well-being and constitution of the patient, thus offering a comprehensive and patient-centered strategy for managing this complex condition. Ferroptosis-inducing agents such as Erastin, ³⁷ RSL3, ³⁸ sorafenib, ³⁹ sulfasalazine, and iron statins, along with modalities like ionizing radiation and cytokine-based approaches that have the potential to induce ferroptosis and inhibit tumor growth, present promising avenues within the realm of TCM for the treatment of HCC. Furthermore, an accumulating body of evidence underscores the potential of TCM in retarding the advancement of HCC by directing its therapeutic focus toward the ferroptosis pathway, as depicted in Figure 2.

Figure 2.

TCM intervention for ferroptosis in HCC. The ferroptosis of HCC cells induced by TCM can effectively inhibit the malignant transformation of HCC, improve patient survival prognosis, and enhance clinical efficacy.

This emerging approach shows promise in reshaping the HCC management landscape by harnessing the intricate mechanisms of ferroptosis for therapeutic benefits. TCM and its active ingredients have a dual regulatory effect on ferroptosis by targeting different signaling pathways: they can both positively regulate the occurrence of ferroptosis and negatively regulate it. Increasing evidence suggests that ferroptosis, as a novel nonapoptotic programmed cell death, plays an important role in the occurrence and development of human diseases such as malignant tumors, and its underlying molecular mechanisms are becoming increasingly clear. For example, sulforaphane, which has anti-inflammatory, antioxidant, and anticancer effects, can alleviate ferroptosis in acute liver failure and prevent the occurrence of HCC. ⁴⁰ Furthermore, the Jiedu Recipe, a prominent TCM formula for treating HCC, has been found to inhibit HCC stemness under hypoxic conditions by targeting the Wnt/β-catenin pathway. ⁴¹ It is well established that aberrant Wnt/β-catenin signaling is closely related to ferroptosis resistance. ⁴² Therefore, we will provide an overview of the role of TCM in the occurrence and development of HCC through ferroptosis and its molecular mechanisms in recent years. We will also discuss the potential clinical applications of ferroptosis and provide references for the promotion of TCM and its use in the prevention and treatment of HCC through ferroptosis (Table 1).

Table 1.

Intervention Effects of TCM in Regulating Ferroptosis in HCC.

TCM	Formula	Function	Reference
Dihydroartemisinin		GSH-dependent antioxidant pathway, lipid peroxidation, and iron metabolism	Wang et al, 43 Su et al, 44 and Cui et al 45
Artesunate		Lipid peroxidation and iron metabolism	Li et al 46
Polyphyllin I		GSH-dependent antioxidant pathway and iron metabolism	Yang et al 47
Curcumin		Iron metabolism	Liu et al 48
Angelica polysaccharide	–	GSH-dependent antioxidant pathway and lipid peroxidation	Liu et al 49
Dehydroabietic acid		Lipid peroxidation and iron metabolism	Xiahou and Han 50
Gallic Acid		GSH-dependent antioxidant pathway	Xie et al 51
Saikosaponin A		GSH-dependent antioxidant pathway	Lan et al 52
Butyrate		Lipid peroxidation and iron metabolism	Yu et al 53
Camptothecin		GSH-dependent antioxidant pathway and iron metabolism	Elkateb et al 54
Plumbagin		GSH-dependent antioxidant pathway	Yao et al 55
Polyphyllin VI		GSH-dependent antioxidant pathway and iron metabolism	Huang et al 56
Rhamnazin		GSH-dependent antioxidant pathway	Mei et al 57
Solasonine		GSH-dependent antioxidant pathway	Jin et al 18
Parthenolide		GSH-dependent antioxidant pathway	Lobianco et al 58
All-trans retinoic acid		GSH-dependent antioxidant pathway	Sun et al 59
Pien-Tze-Huang	–	GSH-dependent antioxidant pathway	Yan et al 60
Esculetin		GSH-dependent antioxidant pathway and iron metabolism	Xiu et al 61
Tiliroside		GSH-dependent antioxidant pathway	Yang et al 62
Withaferin A		GSH-dependent antioxidant pathway	Zhang et al 63
Gentian violet		GSH-dependent antioxidant pathway	Chen et al 64
Caryophyllene Oxide		Iron metabolism	Xiu et al 65
Esculetin		GSH-dependent antioxidant pathway and iron metabolism	Xiu et al 61
Atractylodin		GSH-dependent antioxidant pathway, lipid peroxidation, and lipid peroxidation	He et al 66
Heteronemin		GSH-dependent Antioxidant pathway and iron metabolism	Chang et al 67
Formosanin C		Iron metabolism	Lin et al 68
Haloperidol		GSH-dependent antioxidant pathway and iron metabolism	Bai et al 17

Abbreviations: HCC, hepatocellular carcinoma; TCM, Traditional Chinese Medicine.

Ferroptosis of HCC Induced by Antioxidant Pathways by TCM

Cysteine serves as the key limiting factor in GSH synthesis, with its availability primarily regulated by cystine. The cellular transport of cysteine is facilitated by the transporter protein SLC7A11. Moreover, GSH plays a crucial role as a reactive substrate for GPX4, enabling the breakdown of lipid peroxides. As a result, the impaired antioxidant system in HCC can lead to the accumulation of lipid peroxides and increased vulnerability to ferroptosis. This intricate interplay emphasizes the significance of maintaining a strong antioxidant defense mechanism in the management of HCC.

DHA and Sora inhibit cell energy metabolism in HepG2 cells by reducing oxidative phosphorylation and glycolysis rates, and induce ferroptosis by changing several biochemical parameters, such as increasing the levels of L-ROS, LIP, and MDA, while decreasing the level of GSH. They also reduce the levels of SLC7A11, GCLC, GPX4, and HO-1 proteins. DHA specifically promotes ferroptosis by facilitating the formation of PEBP1/15-LO, enhancing lipid peroxidation, and upregulating PEBP1, which is related to the inhibition of its ubiquitination degradation. DHA could also induce ferroptosis in HCC cells by activating anti-survival UPRs and increasing the expression of CHAC1. Polyphyllin I intervention inhibits the growth, invasion, and spread of HCC cells. It does this by increasing mitochondrial disruption and triggering ferroptosis through the Nrf2/HO-1/GPX4 pathway. Glycyrrhetinic acid has been observed to decrease the expression of ferroptosis-related proteins SLC7A11 and GPX4 in HepG2, doing so by inhibiting the transport of β-catenin from the nucleus to the cytoplasm. The ferroptosis of HCC, brought about by Saikosaponin A, and the subsequent suppression of the expression of the protein SLC7A11, are reliant on the presence of ATF3. Camptothecin enhances the sensitivity of sorafenib and reduces its resistance by enhancing the ferroptosis action of sorafenib. Plumbagin-induced tumor suppression is correlated with the downregulation of GPX4 and the upregulation of apoptosis. Polyphyllin VI inhibits STAT3 phosphorylation, which leads to the inhibition of GPX4 expression. This inhibition of GPX4 induces ferroptosis in HCC cells, ultimately resulting in the suppression of their invasion and metastasis. Rhamnazin exerts a role in inducing ferroptosis in HCC cells by inhibiting the expression of GPX4. Solasonine promotes ferroptosis of HCC by inducing the destruction of the glutathione redox system, which is mediated by GPX4. The compound PZH has shown promising effects in improving the hepatic fibrosis microenvironment and preventing the development of HCC. It achieves this by enhancing ferroptosis in tumor cells through the inhibition of the SLC7A11-GSH-GPX4 axis. Withaferin A increases the expression of Keap1, which helps mitigate the activation of Nrf2 signaling that is associated with EMT and the expression of the ferroptosis-related protein SLC7A11. This suggests that Withaferin A may have the potential in inhibiting EMT and suppressing ferroptosis through its effects on Keap1 and Nrf2 signaling. Gentian violet increases the expression levels of both p53 and its negative regulator MDM2. This upregulation is dependent on the expression of the dehydrogenase/reductase protein Hep27. This signaling cascade involving Gentian violet, Hep27, MDM2, and p53 is thought to play a role in regulating ferroptosis.

Ferroptosis of HCC Induced by Lipid Peroxidation by TCM

Lipid peroxidation plays a crucial role in the occurrence of ferroptosis. One key lipid, phosphatidylethanolamine, containing arachidonic acid or its progeny, such as epinephrine, acts as a pivotal phospholipid initiator, triggering the cascade of ferroptosis within cells. Additionally, PUFAs serve as substrates for mediators involved in lipid signaling, significantly contributing to the regulation of ferroptosis. A key enzyme, ACSL4, governs the composition of lipids and enables the covalent attachment of arachidonic acid or epinephrine through its remarkable catalytic activity. This catalytic process results in the generation of acyl-CoA derivatives, which subsequently undergo esterification by LPCAT3. This orchestrated sequence of events ultimately leads to the progression of ferroptosis, a highly complex and biologically important process.

Artesunate enhances the effect of sorafenib by activating the lysosome, leading to a sequence of reactions that involve the activation of cathepsin B/L in the lysosome, the degradation of ferritin, lipid peroxidation, and ultimately, ferroptosis. A nanocarrier material based on angelica polysaccharide was modified with AA. This was done to selectively enhance ferroptosis in solid tumors by reducing GSH levels under conditions of low oxygen or hypoxia. Butyrate increases the levels of intracellular iron and lipid peroxidation, which in turn speed up the process of ferroptosis. Parthenolide induces tumor cell death by increasing intracellular oxidation levels, making the cells more susceptible to ferroptosis. Tiliroside has the potential to enhance the effectiveness of sorafenib in the treatment of HCC by targeting TBK1 and inducing ferroptosis. Atractylodin has been shown to elicit ferroptosis in HCC by downregulating the expression of GPX4 and FTL proteins, while concurrently upregulating the expression of ACSL4 and TFR1 proteins. Heteronemin, an intriguing marine terpenoid, has been demonstrated to effectively induce both apoptosis and ferroptosis in HCC. These unique cellular processes are mediated through the activation of ROS and the MAPK pathways. Haloperidol, a sigma receptor 1 antagonist, facilitates the induction of ferroptosis in HCC cells.

Ferroptosis of HCC Induced by Iron Metabolism by TCM

Iron constitutes a pivotal trace element within the intricate tapestry of the human organism. Divalent iron ions assume a paramount role, facilitating the transfer of electrons to intracellular oxygen species. This process engenders a milieu wherein intracellular oxygen engages in a transformative dance with lipids, ultimately culminating in the generation of lipid peroxides.

The programmed cell death paths mediated by metal ions, specifically ferroptosis and cuproptosis, could play a crucial role in treating HCC with curcumin. Dehydroabietic acid has shown the ability to bind with CRLS1, ACACA, and TFR1, and could effectively destroy HCC cells by controlling the processes of ferroptosis and lipidosomes, particularly focusing on the metabolism of cardiolipin. Caryophyllene oxide primarily induces cell death in HCC cells through a mechanism known as ferritinophagy-mediated ferroptosis. Esculetin exhibits inhibitory effects on HCC both in vivo and in vitro. It achieves this by activating the NCOA4 pathway, which in turn mediates ferritinophagy. Formosanin C exhibits therapeutic promise against apoptosis-resistant HCC with heightened NCOA4 expression through the process of ferritinophagy, leading to selective degradation of iron-loaded ferritin and subsequent cell death.

Conclusion and outlook

Ferroptosis has garnered significant interest in the realm of preclinical cancer therapy, emerging as a unique, iron-dependent mode of programmed cell death. Our growing comprehension of this intricate process is leading to the exploration of increasing therapeutic possibilities to leverage ferroptosis as a potent target. Amid this context, HCC, being one of the most prevalent and difficult malignancies, remains a substantial therapeutic hurdle despite considerable advancements in relevant treatment methods over recent years. This review has meticulously elucidated the underlying mechanisms of ferroptosis, and underscored the strategic position TCM holds in harnessing ferroptosis as a treatment strategy against HCC. Current research emphasis being primarily at the preclinical cellular and animal stages, the noticeable link between ferroptosis and existing therapeutic alternatives for HCC has stirred significant interest. Therefore, it's crucial to reveal the nuanced manners in which ferroptosis may be employed as a base mechanism in HCC's therapeutic schema. This quest not only enlightens the present but also emerges as an essential focus for future inquiries, promising to bolster our weaponry against this daunting malignancy. Exploring the molecular mechanisms of HCC ferroptosis, including antioxidant pathways, lipid peroxidation, and iron metabolism pathways, along with identifying effective and less toxic natural products from TCM, has the potential to enhance the clinical prognosis for patients with HCC. This offers a theoretical cornerstone for the clinical application and modernization of TCM.