Intracellular iron accumulation is a key driver of ferroptosis. Transferrin-bound Fe³⁺ is internalized and reduced to Fe²⁺, contributing to the labile iron pool (3,4,5,8). Nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy can release stored iron and increase the labile iron pool (10). Excess ferrous iron catalyzes the generation of reactive oxygen species (ROS) via Fenton chemistry, thereby promoting lipid peroxidation. Dysregulation of iron uptake, storage or export enhances ferroptotic sensitivity by increasing oxidative stress.

The execution of ferroptosis depends on the peroxidation of polyunsaturated fatty acid (PUFA)-containing phospholipids in cellular membranes. Acyl-CoA synthetase long-chain family member 4 (ACSL4) and lysophosphatidylcholine acyltransferase 3 participate in remodeling membrane phospholipids and increasing the abundance of peroxidizable lipid substrates (11,12). Iron-dependent enzymatic and non-enzymatic reactions generate lipid peroxides, which accumulate when detoxification systems are impaired (5,8,12).

The system Xc⁻ cystine/glutamate antiporter-glutathione (GSH)-glutathione peroxidase 4 (GPX4) axis represents the central protective mechanism against ferroptosis. System Xc⁻, composed of solute carrier family 7 member 11 (SLC7A11) and SLC3A2, mediates cystine uptake in exchange for glutamate, thereby supporting GSH synthesis. GPX4 utilizes GSH to reduce lipid hydroperoxides into non-toxic lipid alcohols, thereby preventing excessive lipid ROS accumulation and ferroptotic membrane damage (13). Inhibition of system Xc⁻, depletion of GSH or direct suppression of GPX4 activity markedly enhances ferroptotic susceptibility (3,4,5,8).

In addition to the canonical GPX4-dependent pathway, alternative antioxidant systems have been identified. The NADPH-ferroptosis suppressor protein 1 (FSP1)-coenzyme Q10 (CoQ10) axis functions independently of GPX4 to suppress lipid peroxidation (14,15). Furthermore, tumor suppressor p53 can modulate ferroptosis sensitivity, partly through transcriptional repression of SLC7A11, thereby linking ferroptosis to tumor biology (16).

Collectively, ferroptosis is governed by a dynamic interplay between iron metabolism, lipid peroxidation and antioxidant defenses. Disruption of this balance determines cellular sensitivity to ferroptotic cell death. The core molecular mechanisms of ferroptosis are summarized in Fig. 1.

EC, encompassing esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC), remains one of the most lethal GI malignancies worldwide, largely due to late-stage diagnosis and intrinsic chemoresistance (17). Emerging evidence suggests that ferroptosis is involved in EC progression and treatment response, with either tumor-suppressive or resistance-associated effects depending on the molecular context (5,6,7,8,18).

The suppression of ferroptosis represents a critical mechanism by which EC cells sustain chemoresistance. At its core, oncogenic regulators actively orchestrate upregulation of the SLC7A11-GPX4 axis to insulate tumor cells from ferroptotic death. In chemoresistant ESCC, HMGA1 functions as an upstream chromatin remodeler that suppresses ferroptosis-related gene programs and drives cisplatin resistance (18–20). At the post-translational level, ubiquitin-specific peptidase 14-mediated deubiquitination stabilizes GPX4 protein, while protein kinase Cι amplification further reinforces this multi-tiered defense against ferroptotic insults in EC cells (20). Conversely, several interventions have been reported to restore ferroptotic sensitivity by targeting these resistance-associated pathways. Gliotoxin disrupts epigenetic homeostasis by downregulating suppressor of variegation 3–9 homolog 1, unleashing ferroptotic gene programs in ESCC (21), while vitexin porphyrin promotes Fe²⁺ accumulation and ROS amplification alongside GSH depletion and GPX4 suppression, converging on lipid peroxidation-driven ferroptosis (22). In EAC, brusatol dismantles cellular redox defenses through nuclear factor erythroid 2-related factor 2(NRF2) inhibition, sensitizing cells to ferroptotic execution (23). Ferroptosis regulation in EC is also influenced by cancer stem-like properties. Heat shock protein (HSP)27 has been reported to regulate ferroptosis sensitivity in EC stem-like cells; its activation restores GPX4 expression and confers resistance, whereas HSP27 downregulation promotes ferroptosis susceptibility (24). Natural products may provide candidate ferroptosis-modulating agents for EC, but EC-specific evidence remains limited compared with that for other GI tumors (25–27).

Compared with GC, HCC and CRC, evidence for TCM-derived ferroptosis modulators in EC remains limited. Available studies suggest that several natural compounds may affect ferroptosis-related pathways, including GPX4-dependent antioxidant defense, iron metabolism (5,6), lipid peroxidation and mitochondrial redox homeostasis (8,25), with broader implications for natural product drug discovery (26,27). Oridonin has been reported to induce ferroptosis in EC cells by inhibiting the γ-glutamyl cycle and disrupting GSH metabolism (25). However, EC-specific validation, particularly in animal models and clinically relevant systems, remains insufficient.

Taken together, ferroptosis in EC operates as a molecularly stratified, context-sensitive process governed by the interplay of epigenetic regulators, metabolic reprogramming and redox circuitry. The convergence of synthetic compounds and TCM-derived agents on shared ferroptosis checkpoints, particularly the SCL7A11-GPX4 axis and iron-ROS homeostasis, offers a compelling framework for combination strategies that could overcome chemoresistance and improve therapeutic outcomes in EC.

Despite advances in early diagnosis and multimodal treatment, drug resistance remains a principal barrier to therapeutic efficacy in GC (28). Ferroptosis has emerged as a mechanistically compelling entry point in GC biology. Experimental studies have indicated that ferroptosis susceptibility in GC is shaped by GPX4-dependent antioxidant defense, lipid metabolism, receptor signaling and the tumor microenvironment (29,30).

The suppression of ferroptosis in GC is orchestrated through molecularly diverse but functionally convergent mechanisms, all ultimately reinforcing the SCL7A11-GPX4 redox defense axis. Actin-like protein 6A, through its HR structural domain, counteracts ROS accumulation and lipid peroxidation by upregulating glutamate-cysteine ligase catalytic subunit to enhance GSH biosynthesis (29), thereby establishing a chromatin-remodeling-linked antioxidant shield. Similarly, DNA polymerase ε2 accessory subunit upregulation activates NRF2 and its downstream target GPX4 (30), coupling DNA replication fidelity machinery to ferroptosis resistance in GC cells. At the receptor signaling level, 5-hydroxytryptamine (5-HT) receptor 2B upregulation in gastric adenocarcinoma tissues correlates with poor patient prognosis, and its activation by 5-HT suppresses oxidative stress and ferroptosis (31), implicating 5-HT signaling as an unexpected ferroptosis checkpoint.

The tumor microenvironment further amplifies this resistance landscape. Cancer-associated fibroblasts (CAFs) secrete exosomal micoRNA (miR)-522, which silences arachidonate 15-lipoxygenase (ALOX15) to attenuate lipid peroxidation and ROS accumulation, effectively insulating cancer cells from ferroptotic death while simultaneously eroding chemosensitivity (32). Notably, ferroptosis resistance is not uniform across GC subtypes; intestinal-type GC cells deploy epigenetic silencing via DNA methylation to suppress ultra-long-chain fatty acid protein 5 and fatty acid desaturase 1, conferring ferroptotic resistance, whereas mesenchymal-type GC cells, lacking this methylation-based suppression, retain high expression of these enzymes and exhibit markedly greater ferroptosis vulnerability (33). This subtype-specific divergence highlights that ferroptosis sensitivity in GC is determined not merely by individual molecular alterations but by the broader epigenetic and microenvironmental context in which they operate.

Against this resistance backdrop, multiple therapeutic strategies have demonstrated efficacy in restoring or amplifying ferroptotic signaling in GC. Ubiquitin specific peptidase 7 maintains stearoyl-CoA desaturase (SCD) protein stability through deubiquitination in GC cells, and its inhibition by 2-(3,4-dihydro-2H-pyrrolium-1-yl)-3-oxoindan-1-olate triggers SCD degradation, collapsing the unsaturated fatty acid supply required to sustain membrane integrity under oxidative stress and thereby inducing ferroptosis (34). At the metabolic level, apatinib depletes both GPX4 protein and mevalonate-derived coQ10, mechanistically resembling class III ferroptosis inducers and converging on irreversible lipid peroxidation in GC cells (35). The MEK/ERK/serum response factor signaling pathway represents yet another regulatory dimension, governing ferroptosis susceptibility in CagA-positive GC through transcriptional control of alkylglycerone phosphate synthase and 1-acylglycerol-3-phosphate O-acyltransferase 3, enzymes critical for ether lipid biosynthesis and membrane peroxidation substrate availability (36), such that MEK1/2 inhibition selectively blunts ferroptosis sensitivity in this oncogenically defined GC subset. Beyond synthetic agents, the TCM-derived compound polyphyllin B exerts antitumor activity in GC by disrupting iron metabolic homeostasis and promoting lipid peroxidation accumulation (37), exemplifying the capacity of TCM bioactive compounds to engage ferroptosis through multi-target mechanisms. This polypharmacological feature (that is, simultaneously modulating iron trafficking, redox balance and lipid metabolism) confers a mechanistic breadth that single-target agents inherently lack, and positions TCM-derived ferroptosis inducers as rational candidates for combination strategies aimed at overcoming the heterogeneous resistance landscape of GC (38–41).

Collectively, ferroptosis in GC emerges as a molecularly heterogeneous, context-dependent process shaped by the dynamic interplay of chromatin regulation, receptor signaling, tumor microenvironment crosstalk and metabolic reprogramming. The convergence of endogenous resistance mechanisms and exogenous therapeutic interventions, including TCM-derived compounds, on shared ferroptosis checkpoints underscores the necessity of molecularly stratified approaches to fully exploit ferroptotic vulnerabilities across the diverse biological landscape of GC.

HCC is one of the most lethal malignancies worldwide, largely due to late diagnosis, high recurrence rates and resistance to systemic therapies such as sorafenib (42). Given the intrinsic iron-rich environment of the liver and the central role of hepatic metabolism in redox regulation, ferroptosis has emerged as a particularly relevant form of regulated cell death in HCC (3,4,5,8). Notably, HCC cells frequently exhibit elevated iron storage and enhanced lipid peroxidation capacity (3,5,8), suggesting an inherent predisposition toward ferroptotic vulnerability. However, this susceptibility is counterbalanced by robust adaptive antioxidant programs.

In HCC, ferroptosis resistance is primarily maintained through the reinforcement of redox homeostasis and metabolic rewiring. NRF2-related antioxidant signaling represents a central mechanism of ferroptosis resistance in HCC. Elevated translocator protein expression correlates with NRF2 stabilization, promoting transcription of antioxidant and iron-handling genes that collectively suppress ferroptotic signaling (43). This NRF2-dominant state enables tumor cells to buffer lipid peroxidation despite iron accumulation. Metal ion crosstalk further contributes to ferroptosis inhibition. Disruption of COMM domain containing 10 enhances copper accumulation and stabilizes hypoxia-inducible factor 1α (HIF1α), which transcriptionally upregulates ceruloplasmin and SLC7A11 (44). By increasing cystine import and GSH synthesis, this copper-HIF1α-SLC7A11 loop attenuates ferroptosis and confers radioresistance. These findings highlight that ferroptosis suppression in HCC is not solely dependent on iron metabolism but also shaped by broader metal homeostasis.

Metabolic adaptation represents another key mechanism. Partner of NOB1 homolog-driven autophagy supports system Xc⁻ activity and sustains intracellular cysteine pools required for GSH synthesis. Through this GSH-centered metabolic reprogramming, HCC cells maintain GPX4 activity and resist lipid ROS accumulation (45). Conversely, disruption of these antioxidant defenses renders HCC cells highly susceptible to ferroptosis. The methyltransferase 9, His-X-His N1(π)-histidine (METTL9)-SLC7A11 axis represents one such vulnerability. METTL9 deficiency reduces SLC7A11 expression, weakens cystine uptake and enhances lipid peroxidation, thereby suppressing tumor growth through ferroptosis (46). Glutaminase 2, typically promoting α-ketoglutarate (αKG) production and mitochondrial ROS generation, is frequently silenced by promoter hypermethylation in HCC (47). Restoration of glutamine catabolism or αKG flux enhances oxidative stress and promotes ferroptosis, suggesting that metabolic reactivation strategies may overcome tumor resistance.

Ferroptosis is closely linked to therapeutic response in HCC. Phosphoseryl-tRNA kinase supports selenocysteine incorporation into GPX4; its depletion impairs GPX4 activity and enhances chemotherapy-induced ferroptosis (48). Reduced MCF2L expression sensitizes HCC cells to ferroptosis through PI3K/mTOR-related signaling (49). Sorafenib has been reported to induce iron-dependent cell death in HCC cells, and ferroptosis contributes to its antitumor activity (50). Artesunate synergizes with sorafenib to induce ferroptosis in HCC (51). Given the iron-rich hepatic environment, artemisinin derivatives, which enhance iron-dependent oxidative injury by regulating iron homeostasis in cancer cells (52), may hold particular therapeutic relevance for HCC (50).

Several natural compounds further illustrate the therapeutic potential of ferroptosis induction in HCC. Cyclovirobuxine D suppresses GPX4 and FSP1-associated ferroptosis defense pathways, thereby enhancing lipid peroxidation (52). Celastrol liposomes induce ferroptosis and apoptosis by targeting voltage-dependent anion channel 2 and amplifying mitochondrial oxidative stress (53). Gallic acid promotes ferroptosis in HCC through inactivation of Wnt/β-catenin signaling (54).

Taken together, ferroptosis in HCC is governed by a dynamic balance between iron-driven oxidative stress and compensatory antioxidant programs. Therapeutic strategies that dismantle multiple layers of ferroptosis resistance may provide a rational approach to improving treatment outcomes in this metabolically complex malignancy.

CRC is among the most prevalent malignancies worldwide and remains a leading cause of cancer-related mortality (1,2). In CRC, emerging evidence indicates that ferroptosis plays a context-dependent role and ferroptosis resistance is frequently mediated through upregulation of the SLC7A11-GSH-GPX4 axis. Uridine-cytidine kinase 1 like 1 enhances the NRF2-dependent transcription of SLC7A11, thereby strengthening cystine uptake and GSH synthesis (55). Similarly, HtrA serine peptidase 1 interacts with SLC7A11 and promotes its expression, contributing to chemoresistance by limiting lipid ROS accumulation (56). The tumor microenvironment also plays a critical role. Adipocyte-derived exosomes containing microsomal triglyceride transfer protein (MTTP) and proline rich acidic protein 1 complexes suppress zinc finger E-box-binding homeobox 1 expression, leading to increased GPX4 and SCL7A11 levels (57). In CRC cells, this exosome-mediated metabolic reprogramming reduces PUFA availability and lipid peroxidation, thereby diminishing ferroptosis susceptibility and promoting resistance to oxaliplatin.

Mitochondrial regulatory factors further modulate ferroptotic sensitivity. In CRC cells, elevated methyltransferase like 17 expression enhances mitochondrial function and correlates with ferroptosis resistance, whereas its depletion disrupts redox balance and increases lipid peroxidation (58). Additionally, the activating transcription factor 3-cystathionine β-synthase signaling axis influences cysteine metabolism and mitochondrial tricarboxylic acid cycle activity, illustrating how metabolic flexibility determines CRC cell survival under ferroptotic stress (59). Targeting the SLC7A11-centered antioxidant system represents a major strategy for ferroptosis induction in CRC. Vitamin D and sodium butyrate reduce SLC7A11 expression and promote lipid peroxidation, with synergistic effects observed when combined with classical ferroptosis inducers (60). MicroRNA (miR)-mediated regulation also contributes to ferroptosis induction in CRC. miR-148a-3p suppresses SLC7A11, increases ROS accumulation and promotes ferroptotic cell death while exerting limited toxicity in normal epithelial cells (61).

Natural compounds further expand the ferroptosis-targeting landscape in CRC. Erianin induces autophagy-dependent ferroptosis characterized by iron accumulation and mitochondrial dysfunction, particularly in KRAS-mutant CRC (62). Puerarin promotes NCOA4-mediated ferritinophagy, increasing intracellular labile iron pools (63). Solanine activates the arachidonate 12-lipoxygenase, 12R type/adenylyl cyclase type 4 axis to amplify lipid peroxidation (64). Other agents, including osthole, ginsenoside Rh3 and fucoidan, modulate interconnected signaling pathways such as AMP-activated protein kinase/Akt, signal transducer and activator of transcription 3 (STAT3)/p53/NRF2 and ferroptosis-related biotarget networks, ultimately converging on ferroptosis execution (65–67).

Overall, ferroptosis in CRC reflects a balance between metabolic adaptability and oxidative stress burden. Interventions that disrupt cysteine metabolism, amplify lipid peroxidation or impair mitochondrial redox homeostasis hold promise for overcoming chemoresistance and improving outcomes in CRC.

Beyond esophageal, gastric, hepatic and colorectal cancer, ferroptosis dysregulation is also evident in other digestive system malignancies, particularly pancreatic ductal adenocarcinoma (PDAC), a tumor characterized by profound metabolic reprogramming and a dense desmoplastic microenvironment (68,69).

In PDAC, EP300-mediated acetylation of HSPA5 has been reported to promote ferroptotic vulnerability, indicating that epigenetic regulation of chaperone function may influence redox homeostasis and ferroptosis sensitivity (70). More notably, the tumor microenvironment plays a decisive role. CAFs, a dominant stromal component in pancreatic cancer, remodel cysteine metabolism to sustain GSH synthesis in tumor cells (71). By supplying metabolic substrates or regulating redox-related signaling pathways, CAFs effectively buffer lipid peroxidation and reduce ferroptotic sensitivity (71). This microenvironment-dependent ferroptosis suppression mirrors observations in gastric and colorectal cancer (29,57), suggesting that stromal metabolic support represents a conserved resistance mechanism across digestive malignancies.

Collectively, these findings indicate that ferroptosis regulation in digestive system tumors is governed not only by intrinsic tumor cell pathways but also by epigenetic modulation and metabolic crosstalk within the tumor microenvironment. The balance between iron-driven oxidative stress and adaptive antioxidant programs determines whether ferroptosis functions as a tumor-suppressive mechanism or is actively restrained to promote tumor survival. Understanding these context-dependent regulatory networks may facilitate the rational integration of ferroptosis-targeted strategies with chemotherapy, radiotherapy and immunotherapy in digestive tract malignancies.

The intensity and duration of lipid peroxidation are central determinants of ferroptosis outcome. Sustained accumulation of lipid ROS causes irreversible membrane damage and ferroptotic cell death, particularly when the system Xc⁻/GSH/GPX4 axis or the FSP1/CoQ10 pathway is impaired (74,75). This mechanism underlies the antitumor effects of several ferroptosis-inducing treatments in GI cancer, including sorafenib-based therapy in HCC and ferroptosis-inducing compounds in gastric and colorectal cancer (23,37,50). However, sublethal lipid peroxidation may have the opposite consequence. Moderate or transient oxidative stress can function as a selective pressure that activates adaptive antioxidant responses. NRF2 activation, increased SLC7A11 expression, enhanced cystine uptake, elevated GSH synthesis and restoration of GPX4 activity collectively increase redox tolerance and allow tumor cells to survive subsequent ferroptotic insults (17,18,30,43).

The tumor microenvironment profoundly influences ferroptosis sensitivity. Stromal cells, including CAFs, adipocytes, immune cells and endothelial cells, can reshape the redox and metabolic state of tumor cells. In GC, CAF-derived exosomal miR-522 suppresses ALOX15-mediated lipid peroxidation and promotes acquired chemoresistance (32). In CRC, adipocyte-derived exosomal MTTP suppresses ferroptosis and contributes to oxaliplatin resistance (57). In pancreatic cancer, CAF-mediated reprogramming of cysteine metabolism sustains GSH production and protects tumor cells from ferroptotic death (71).

By contrast, ferroptotic tumor cell death may also influence antitumor immunity. CD8+ T cells have been shown to promote tumor ferroptosis during cancer immunotherapy (72). Radiation-induced tumor suppression is also closely associated with ferroptosis in certain contexts (73). Therefore, ferroptosis should be viewed as a regulator of tumor-stroma-immune crosstalk rather than merely a single-cell death event.

Ferroptosis sensitivity differs among GI tumor types and among molecular subtypes within the same cancer. HCC develops in an iron-rich and metabolically active organ, making iron metabolism and oxidative stress particularly relevant. However, HCC cells frequently acquire NRF2-dependent antioxidant defenses (43). GC demonstrates subtype-specific ferroptosis sensitivity, and PUFA biosynthesis pathways influence whether tumor cells are vulnerable or resistant to lipid peroxidation (33). CRC, especially in KRAS-mutant contexts, may exhibit altered lipid metabolism and increased oxidative stress, creating potential ferroptotic vulnerabilities (62,65). In EC, ferroptosis is closely linked to chemoresistance, cancer stem-like properties and SCL7A11-GPX4 regulation (10,12,16).

A number of anticancer treatments can induce ferroptosis directly or indirectly. Sorafenib, radiotherapy, immunotherapy and several natural compounds have been reported to promote ferroptosis by suppressing antioxidant defenses, increasing iron-dependent ROS production or amplifying lipid peroxidation (37,38,72,73). In treatment-responsive tumors, ferroptosis induction enhances tumor cell killing and may overcome apoptosis resistance.

Nevertheless, therapy-induced ferroptotic stress may also drive adaptive resistance if the intensity or duration of ferroptosis induction is insufficient. Indeed, sublethal lipid peroxidation can activate adaptive antioxidant responses, including NRF2 activation and upregulation of SLC7A11, GPX4 and FSP1 (29,30,43,55), which increase redox tolerance and allow tumor cells to survive subsequent ferroptotic insults. It is therefore hypothesized that, over time, this selective pressure may enrich resistant clones with stronger redox buffering capacity and metabolic flexibility. Accordingly, ferroptosis-based therapy requires careful optimization of drug combinations, dosing intensity, treatment timing and patient selection.

The most common mechanism by which herbal compounds induce ferroptosis involves disruption of the canonical antioxidant defense system. Several phytochemicals, including oridonin, tanshinone IIA, polyphyllin B, gallic acid and emodin, reduce GPX4 expression or activity, thereby impairing lipid peroxide detoxification (25,37). Others, such as quercetin, baicalin, asiaticoside and resveratrol, suppress SLC7A11 expression either directly or via upstream signaling pathways including NRF2, STAT3 or Wnt/β-catenin (38–40). By limiting cystine uptake and GSH synthesis, these agents weaken the cellular redox buffering capacity and sensitize tumor cells to lipid ROS accumulation. Notably, a number of these compounds regulate upstream transcriptional programs rather than directly inhibiting GPX4 enzymatic activity. This indirect modulation may enhance ferroptotic susceptibility while simultaneously influencing additional oncogenic pathways, reflecting the polypharmacological nature of herbal extracts.

A second mechanistic cluster involves alteration of intracellular iron homeostasis. Compounds targeting iron metabolism constitute another important category of herbal or natural ferroptosis modulators. Artesunate and other artemisinin derivatives can enhance iron-dependent oxidative injury through their iron-reactive endoperoxide bridge, whereas puerarin has been reported to promote NCOA4-mediated ferritinophagy and increase the intracellular labile iron pool (50,51,63). Erianin and cyclovirobuxine D also induce ferroptosis-associated iron accumulation and lipid peroxidation, although their upstream mechanisms may differ among tumor models (52,62). Elevated intracellular Fe²⁺ accelerates Fenton reactions and lipid peroxidation, thereby amplifying ferroptotic signaling.

NRF2-mediated antioxidant signaling represents a central ferroptosis resistance pathway across GI tumors (43,66). Several herbal compounds attenuate NRF2 activity either directly or indirectly. Quercetin regulates the NRF2/GPX4 axis in GC cells (38), while ginsenoside Rh3 modulates STAT3/p53/NRF2 signaling in CRC cells (66). Inhibition of NRF2 not only promotes ferroptosis but may also reverse chemoresistance, particularly in HCC and CRC. Given that chronic NRF2 activation contributes to therapy resistance, targeting this axis through multi-target natural compounds may provide a strategy to dismantle adaptive redox defense networks.

Beyond the canonical GPX4-dependent pathway, some herbal extracts induce ferroptosis by modulating mitochondrial function and metabolic flux. Erianin and celastrol increase mitochondrial ROS production and disrupt membrane potential, thereby intensifying lipid peroxidation (53,62). For example, oridonin inhibits the γ-glutamyl cycle to disrupt glutamine-dependent GSH biosynthesis, thereby limiting substrate availability for antioxidant regeneration (25). Additional compounds may also modulate fatty acid synthesis and the mevalonate pathway to alter membrane lipid composition and coenzyme Q10 pools, although direct evidence from herbal extracts remains limited (51,78,79). This metabolic reprogramming underscores the interconnected nature of ferroptosis with broader tumor bioenergetics and suggests that herbal compounds may act as metabolic stress amplifiers rather than single-pathway inhibitors.