The conceptual foundation of ferroptosis was laid in 2003 when Dolma et al. identified erastin as a novel compound selectively lethal to RAS-mutated BJeLR fibroblasts through rapid, irreversible cytotoxicity (Dolma et al., 2003). Subsequent studies revealed the iron-dependent non-apoptotic death mechanism of RAS-mutated cancer cells induced by small molecules RSL3 and RSL5 (Yang and Stockwell, 2008). The term “ferroptosis” was formally proposed in 2012, with mechanistic studies demonstrating erastin’s dual action in HT-1080 fibrosarcoma models: mitochondrial voltage-dependent anion channel (VDAC) modulation and inhibition of the Xc system subunit solute carrier family 7 member 11 (SLC7A11), leading to glutathione depletion and iron-dependent lipid ROS accumulation (Dixon et al., 2012).

A pivotal 2014 study established glutathione peroxidase 4 (GPX4) as the central regulator of ferroptosis, with therapeutic implications validated in tumor xenografts (Yang et al., 2014). Concurrently, p53 was shown to enhance ferroptosis sensitivity by suppressing SLC7A11-mediated cysteine (Cys) uptake, while its acetylation-deficient mutant (p53 3 KR) retained regulatory capacity over ferroptosis under oxidative stress (Jiang et al., 2015). In 2017, acyl-CoA synthetase long-chain family member 4 (ACSL4) was identified as essential for ferroptosis execution by enriching ω6 polyunsaturated fatty acid (PUFA)-containing membranes (Doll et al., 2017). Subsequent work in 2019 uncovered an independent glutathione-bypassing ferroptosis suppression axis mediated by ferroptosis suppressor protein 1 (FSP1) via Coenzyme Q10 (CoQ10) (Doll et al., 2019).

Recent advances have uncovered novel regulatory networks in ferroptosis. The nuclear factor erythroid-2 related factor 2 (Nrf2)-HECT and RLD domain containing E3 ubiquitin protein ligase 2 (HERC2) axis has been shown to modulate cellular iron homeostasis and ferroptosis sensitivity through vesicle associated membrane protein 8 (VAMP8) regulation (Anandhan et al., 2023). Pharmacological targeting of emopamil binding protein (EBP) to block 7-dehydrocholesterol (7-DHC) biosynthesis demonstrates potent ferroptosis induction and antitumor efficacy, with pathway components including cytochrome p450 family 51 subfamily A member 1 (CYP51A1), EBP, and sterol C5-desaturase (SC5D) emerging as potential ferroptosis inhibitors (Freitas et al., 2024; Li Y. et al., 2024). These discoveries have propelled ferroptosis research from basic biological characterization to therapeutic exploration in diverse pathologies including oncology, neurodegenerative disorders, and ischemia-reperfusion injury, offering innovative perspectives for disease mechanism elucidation and intervention strategies (Chen X. et al., 2021; Ju et al., 2023; Wang Y. et al., 2023).

Ferroptosis manifests distinct morphological alterations that differentiate it from other cell death modalities. Morphologically, ferroptotic cells exhibit cytoplasmic shrinkage, contrasting with apoptotic cell contraction through its association with intracellular lipid peroxide accumulation rather than membrane blebbing. Crucially, these cells preserve plasma membrane integrity and nuclear architecture, lacking characteristic apoptotic features such as chromatin margination, plasma membrane blebbing, or apoptotic body formation (Yagoda et al., 2007; Dixon et al., 2012; Yan H. et al., 2021), unlike autophagic cell death, they show neither double-membrane autophagic vesicles nor compromised membrane integrity (Liang et al., 2019). The pathognomonic ultrastructural features include mitochondrial atrophy with reduced cristae density and increased membrane condensation (Dixon et al., 2012; Stockwell et al., 2017) (Table 1; Figure 2).

Iron overload has been shown to impair MM cell proliferation, an effect reversible by the ferroptosis inhibitor ferrostatin-1. High-dose ferric ammonium citrate (FeAC) triggers MM cell death with concurrent elevation of MDA - a lipid peroxidation byproduct and hallmark of ferroptosis, establishing iron metabolism as a critical modulator in MM pathophysiology (Bordini et al., 2020; Camiolo et al., 2020). Mechanistically, free iron accumulation induces dose-dependent aggregation of polyubiquitinated proteins in iron-sensitive MM H929 cells, while suppressing chymotrypsin-like proteasomal activity in cell lysates. This dual mechanism suggests that iron overload may potentiate proteasome inhibitor efficacy through lipid oxidation and proteostasis disruption, providing a rationale for combinatorial therapeutic strategies (Bordini et al., 2020; Camiolo et al., 2020). Iron homeostasis dysregulation in MM is further linked to altered hepcidin expression patterns. Although hepcidin (a hepatic iron-regulatory peptide) typically restricts systemic iron release (Nemeth and Ganz, 2023), MM patients exhibit paradoxical hepcidin downregulation or functional impairment during iron overload, creating a self-reinforcing cycle of iron accumulation that exacerbates disease progression (Maes et al., 2010; Banaszkiewicz et al., 2022).

Emerging evidence demonstrates that andrographolide, a natural bioactive compound, induces ferroptosis in MM cells via P38-mediated suppression of the Nrf2/heme oxygenase-1 (HO-1) signaling axis, thereby triggering oxidative stress (Li W. et al., 2023). Mechanistically, Nrf2 serves as the master transcriptional regulator of antioxidant responses, orchestrating cellular iron homeostasis, redox balance, and mitochondrial function through transcriptional regulation of FPN1, GPX4, and HO-1. Crucially, Nrf2 knockout models exhibit diminished SLC7A11 and HO-1 protein expression, which potentiates ferroptotic susceptibility (Dong et al., 2020).

Beclin-1, a core autophagy-related protein, drives autophagosome formation, while UNC-51 like kinase 1 (ULK1) coordinates autophagic initiation through its kinase complex (Kim et al., 2011). Notably, protein phosphatase 2A (PP2A) and AMP-activated protein kinase (AMPK) modulate the phosphorylation status of Beclin-1 to regulate autophagic flux (Peris et al., 2023). PP2A specifically dephosphorylates Beclin-1 at Ser90, whereas AMPK–activated under energy stress–phosphorylates ULK1 to initiate autophagy, and targets Beclin-1 at Ser91/Ser94 residues (Kim et al., 2013; Park et al., 2023). Functionally, the PP2A-AMPK axis orchestrates autophagic-ferroptotic crosstalk in MM cells. PP2A activation via dephosphorylation of its catalytic subunit C at Tyr307 induces AMPK inactivation through Thr172 dephosphorylation. This cascade attenuates eukaryotic elongation factor 2 kinase (eEF2k) activity, thereby relieving its inhibition of eEF2 to enhance energy expenditure and drive dual autophagic-ferroptotic cell death (Zhong et al., 2020). CRISPR/Cas9-mediated knockout of autophagy regulators ATG5/ATG7 in RPMI-8226 MM cells significantly increased cell viability compared to wild-type controls upon RSL3-induced ferroptosis, confirming autophagy’s synergistic role in ferroptotic execution (Li and Lyu, 2024).

The interplay between ferroptosis and epigenetic regulation has garnered increasing attention due to their shared associations with oxidative stress and dysregulated iron metabolism. Induction of ferroptosis in MM cells upregulates key genes implicated in cellular stress, death, inflammation, and fatty acid metabolism, including ferritin heavy chain 1 (FTH1), HO-1, and SLC7A11. Studies have demonstrated that ferroptosis induction in MM cells triggers DNA methylation and histone modification changes associated with cellular senescence. Logie et al. revealed that MM1 cells exhibit sensitivity to both the ferroptosis inducer RSL3 and epigenetic reprogramming. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis identified the formation of non-heme iron-histone complexes and altered histone modifications linked to DNA repair and senescence. Using EPIC BeadChip profiling, the authors observed significant DNA methylation alterations in ferroptotic MM cells, enriched in genes regulating cell cycle progression and senescence, such as nuclear receptor subfamily 4 group A member 2 (NR4A2). These findings highlight the connection between ferroptosis and epigenomic stress responses, underscoring the therapeutic potential of ferroptosis-inducing agents (Logie et al., 2021).

Emerging evidence indicates that the crosstalk between bone marrow mesenchymal stromal cells (BMSCs) and MM cells enhances ferroptosis susceptibility in the latter. BMSCs elevate intracellular iron levels in MM cells, thereby activating steroid biosynthesis pathways such as lanosterol production. Lanosterol, a major source of ROS in MM cells, is regulated by the CD40 ligand (CD40L)-CD40 receptor interaction, which serves as a critical signaling axis. BMSCs modulate the CD40/CD40L pathway to influence iron homeostasis and lanosterol synthesis in MM cells, driving ROS accumulation and ferroptosis (Jiang et al., 2024). A recent study further revealed that leukocyte immunoglobulin-like receptor B1 (LILRB1), through complex formation with other proteins, promotes low-density lipoprotein and cholesterol uptake. LILRB1 deficiency disrupts cholesterol uptake but activates compensatory cholesterol biosynthesis to maintain cellular cholesterol homeostasis. This shift reduces levels of the anti-ferroptotic metabolite squalene, rendering MM cells more prone to ferroptosis. Given its role in safeguarding MM cells against ferroptosis via cholesterol regulation, LILRB1 represents a promising therapeutic target (Xian et al., 2024).

A recent study revealed that mitochondrial metabolic kinase PCK2 phosphorylates and activates ACSL4, driving phospholipid remodeling linked to ferroptosis. Tumor-reprogrammed cells (TRCs), characterized by stem-like properties, downregulate PCK2 expression to adopt a ferroptosis-resistant state, suggesting that TRCs evade radio- and chemotherapy by reducing ferroptosis susceptibility. These findings highlight novel insights into ferroptosis in malignant tumors (Li Z. et al., 2024). Fu et al. investigated the clinical and biological relevance of ferroptosis-related genes in MM. Their prognostic model underscored the critical role of ferroptosis in MM patient outcomes. In vitro experiments demonstrated synergistic antitumor efficacy of erastin and doxorubicin, mediated by GPX4 degradation and excessive ROS production, which collectively reduced viability of NCI-H929 and RPMI-8226 cells (Fu et al., 2022). Furthermore, glutamine blockade combined with radiotherapy (RT) induces immunogenic ferroptosis in tumor cells. Mechanistically, RT activates the interferon signaling pathway to upregulate interferon regulatory factor 1 (IRF1), an effect amplified by glutamine inhibition. IRF1 drives transferrin receptor expression, elevates intracellular Fe²⁺ levels, and disrupts iron homeostasis, thereby promoting ferroptosis. The therapeutic potential of this axis in hematologic malignancies warrants further exploration (Song A. et al., 2024) (Figure 4).

The partial inhibition of cell death by Ferrostatin-1, Liproxstatin-1, or Deferoxamine, alongside evidence that natural product extracts induce MM cell death, implicates ferroptosis in MM cell demise. This further highlights plant-derived extracts as promising tools for triggering ferroptosis in MM.

Shikonin (SHK), a natural compound isolated from Lithospermum erythrorhizon roots, exhibits diverse bioactivities, including antioxidant, anti-inflammatory, and antitumor effects, and functions as a proteasome inhibitor and necroptosis inducer (Guo et al., 2019; Guo et al., 2023 Y.; Yan et al., 2023). Shikonin exerts anti-angiogenic effects by downregulating the PI3K/AKT and MAPK signaling pathways, and also displays anticancer activity by targeting ROS (Anti-angiogenic effect of Shikonin, 2020). Studies demonstrate that SHK treatment promotes lactate dehydrogenase release, triggers cell death, induces oxidative stress, and elevates ferrous iron and lipid peroxidation levels. Notably, ferroptosis inhibitors reverse SHK-induced cytotoxicity, confirming ferroptosis involvement. Further mechanistic studies revealed that glutamic-oxaloacetic transaminase 1 (GOT1) serves as a key mediator of SHK-driven ferroptosis by promoting ferritinophagy. These findings underscore SHK’s potential as a therapeutic agent for MM (Li W. et al., 2022).

Apigenin (Api), an edible plant-derived flavonoid, has been recognized as an antitumor agent in numerous experimental and biological studies. It demonstrates cytostatic and pro-apoptotic effects across various malignancies through modulation of multiple signaling pathways (Imran et al., 2020; Jiang Z.-B. et al., 2021; Shi et al., 2023; Sudhakaran et al., 2023; Naponelli et al., 2024). A recent study demonstrated that Api significantly inhibits the progression of bladder cancer by targeting VEGF-β (Apigenin inhibits recurrent bladder cancer, 2025). In addition, it has shown potential therapeutic effects against viral infections (Lee et al., 2023). Notably, our investigation reveals that Api induces myeloma cell apoptosis via the STAT1/COX-2/iNOS signaling axis, demonstrating marked growth inhibition in MM cells with the most pronounced concentration-dependent effect observed in NCI-H929 cells. Importantly, pretreatment with ferrostatin-1 and deferoxamine attenuated Api’s efficacy on NCI-H929 cells by over threefold, strongly suggesting the potential involvement of ferroptosis-related pathways in Api-mediated MM cell death. Further mechanistic investigations are warranted to fully elucidate this regulatory network (Adham et al., 2021a).

Artesunate (ART), a water-soluble hemisuccinate derivative of dihydroartemisinin (DHA), originates from artemisinin–an active compound isolated from Artemisia annua with extensive traditional Chinese medicinal applications and current use as a frontline antimalarial agent (Qian et al., 2021; Strik et al., 2024). ART exhibits both anticancer activity and cytotoxicity against solid tumors and leukemias, having been applied as an adjuvant therapy for diverse malignancies (Vakhrusheva et al., 2022; Hill et al., 2023; Fan et al., 2024). ART exerts its antitumor effects through multiple pathways, including PPARγ-SCD and PI3K/AKT/FKHR signaling (Xu et al., 2022; FABP5, 2024). Liang et al. investigated ART’s effects on cellular growth, ROS generation, Fe²⁺ levels, lipid peroxidation, and ferroptosis-related gene expression, while further exploring ferroptosis mechanisms in MM cells and their association with sterol regulatory element-binding protein 2 (SREBP2) nuclear localization. ART treatment upregulated ROS, Fe²⁺, and lipid peroxidation levels while suppressing MM cell growth, concomitant with increased ACSL4 expression and decreased GPX4 levels. Notably, ART-induced cell death was reversed by ferroptosis inhibitors ferrostatin-1 (Fer-1) and deferoxamine (DFO). Mechanistically, ART suppressed nuclear localization of SREBP2 in MM cells, accompanied by downregulation of IPP and GPX4, suggesting its capacity to trigger ferroptosis through SREBP2 nuclear localization inhibition and subsequent IPP/GPX4 suppression (Liang et al., 2023).

Eclipta prostrata is a herbaceous plant, and its aerial parts are used as traditional medicine. In traditional Chinese medicine, Eclipta prostrata is employed to treat bleeding, liver diseases, kidney injuries, and snake bites (Fang et al., 2015; Tian et al., 2023). Modern pharmacological studies have shown that Eclipta prostrata exhibits various biological activities, such as anti - tumor, anti - snake venom, anti - inflammatory, antioxidant, and hypolipidemic effects (Timalsina and Devkota, 2021; Yang J. et al., 2023). Its extracts have been found to promote osteogenic differentiation of bone marrow mesenchymal stem cells by targeting METTL3-mediated m6A RNA methylation (Tian et al., 2023). Li et al. found that the ethanol extract of Eclipta prostrata (EEEP) could inhibit the growth of MM cells and induce cell death both in vitro and in vivo. EEEP triggers ferroptosis in MM cells by promoting the accumulation of MDA and Fe²⁺, lipid peroxidation, and inhibiting GSH. Mechanistically, EEEP - induced lipid peroxidation and MDA accumulation were blocked by the Nrf2 activator NK - 252. EEEP regulates the kelch-like ECH-associated protein 1 (Keap1)/Nrf2/HO - 1 axis and stimulates ferroptosis in MM cells (Li W. et al., 2024).

Thymus vulgaris L. is an important plant that can be used both medicinally and as food. It has demonstrated various pharmacological effects in both traditional medicine and modern medical research. Its main active components include thymol, carvacrol, flavonoids, and volatile oils (Bolatli et al., 2023; Zhou et al., 2023). Arctium lappa L. belongs to the Asteraceae family and has been widely used in traditional Chinese medicine (TCM). It is rich in highly - recognized bioactive metabolites with antioxidant, anticancer, and neuroprotective activities (Yang et al., 2021). Additionally, Arctium lappa L. also shows significant value in nanomedicine applications (Yosri et al., 2023). A study by Adham et al. found that the extracts of Thymus vulgaris (TCF) and Arctium lappa (ACF) can induce cell - cycle arrest and ferroptosis in MM cells and leukemia cells. The researchers observed that myeloma NCI - H929 cells were significantly sensitive to the chloroform fractions of TCF and ACF, and ferroptosis inhibitors eliminated the cytotoxicity of TCF and ACF extracts (Adham et al., 2020).

Andrographolide (AP), a diterpenoid lactone isolated from Andrographis paniculata, is the main component of this plant and exhibits a wide range of pharmacological effects. Multiple studies have demonstrated its potent antitumor activity (Li et al., 2020b; Li et al., 2024 J.; Jiaqi et al., 2023). Andrographolide promotes ferroptosis by inducing mitochondrial dysfunction, thereby inhibiting the development and progression of non-small cell lung cancer (Jiaqi et al., 2023). Research has found that AP can induce the death of MM cells, cause G0/G1 cell - cycle arrest, and trigger oxidative stress responses. These phenomena are accompanied by an increase in the levels of Fe²⁺ and lipid peroxidation in both the cytoplasm and mitochondria. Further research shows that AP may block the Nrf2/HO - 1 signaling pathway by activating P38, thereby inducing ferroptosis. Additionally, the use of ferroptosis inhibitors can rescue the MM cell death induced by AP, indicating a close relationship between AP - induced MM cell death and the ferroptosis pathway (Li W. et al., 2023).

Ginsenoside Rh4 is an active compound extracted from ginseng. It belongs to protopanaxatriol - type ginsenoside saponins and exhibits a variety of pharmacological activities (Wang et al., 2024). It has been proven to improve antibiotic - induced gut microbiota dysbiosis and intestinal inflammation and inhibit the growth of various tumors (Wu et al., 2018; Dong et al., 2023; Jiang et al., 2023; Bai et al., 2024). Ginsenoside Rh4 suppresses the progression of colorectal cancer by modulating gut microbiota-mediated bile acid metabolism. It also inhibits tumor metastasis by targeting signaling pathways such as Wnt/β-catenin and TGF-β/Smad2/3 (Chen et al., 2022a; Bai et al., 2024). A study by Ying et al. found that ginsenoside Rh4 can inhibit the proliferation of MM cells, induce cell apoptosis, promote cell - cycle arrest, etc., and play a key role in inducing ferroptosis in MM cells (Ying et al., 2023). This process may be related to the inhibition of Sirtuin 2 (SIRT2) expression in MM cells by ginsenoside Rh4. SIRT2 regulates the activity of lipid - peroxidation - related enzymes to reduce the occurrence of ferroptosis and may also participate in regulating the ferroptosis sensitivity of myeloma cells by affecting lipid metabolism and antioxidant regulation (Feng et al., 2024).

Fumaria officinalis is a traditional herbal medicine containing various active components and exhibits multiple pharmacological effects such as antioxidant, antibacterial, anti - inflammatory and antispasmodic, as well as immunomodulatory activities (Raafat and El-Zahaby, 2020; Shah et al., 2024). The chloroform and ethyl acetate (EF) fractions of the Fumaria officinalis extract show significant cytotoxic effects on human acute lymphoblastic leukemia cells and MM cells. Among them, EF induces autophagic cell death, while chloroform can stimulate iron - dependent cell death (Adham et al., 2021b).

Nitidine chloride (NC) is an alkaloid extracted from the dried roots of Zanthoxylum nitidum, a plant of the Rutaceae family. It exhibits various pharmacological activities, including antitumor, anti-inflammatory, antimalarial, and antioxidant effects (Lu et al., 2022). NC has been reported to induce caspase-3/GSDME-dependent pyroptosis in lung cancer by inhibiting the PI3K/Akt pathway (Yu et al., 2022). In multiple myeloma (MM), ATP-binding cassette sub-family B member 6 (ABCB6) has been identified as a key protein mediating ferroptosis resistance by maintaining glutathione (GSH) homeostasis and activating the PI3K/AKT signaling pathway. NC targets ABCB6, suppresses the PI3K/AKT pathway, and induces ferroptosis in MM cells (Yin et al., 2023).

Huachansu Injection is derived from the dried skin of the Bufo gargarizans and has traditionally been used for its detoxifying, anti-inflammatory, and analgesic properties. It is commonly applied in the treatment of advanced-stage cancers and chronic hepatitis B. Huachansu has been shown to inhibit liver cancer cell growth by reducing the activity and expression of glucose-6-phosphate dehydrogenase (G6PD), thereby disrupting the pentose phosphate pathway (Wu Q. et al., 2024). It can also induce apoptosis in gastric cancer cells by increasing ROS levels and suppressing proteasome activity (Deng et al., 2024). Yang et al. were the first to demonstrate that Huachansu Injection induces ferroptosis in multiple myeloma (MM) via the NRF2/HO-1 signaling pathway. Specifically, Huachansu promotes nuclear translocation of NRF2, which activates the transcription of antioxidant genes such as HO-1. HO-1 catalyzes the degradation of heme, leading to the release of free iron, which triggers the Fenton reaction and the accumulation of lipid peroxides such as MDA, ultimately initiating ferroptosis. Moreover, Huachansu downregulates the expression of SLC7A11 and GPX4, weakening the cellular capacity to eliminate lipid peroxides and thereby preventing the suppression of ferroptosis (Yang et al., 2025) (Table 2).

In MM cells, high proteasome activity is a crucial factor for degrading misfolded immunoglobulins to ensure cell survival. As a proteasome inhibitor, bortezomib has been clinically used to treat patients with MM. Bortezomib exerts its therapeutic effects in MM by binding to the β5 subunit of the 26S proteasome to inhibit the ubiquitin–proteasome pathway, blocking activation of the Nuclear factor kappa-light-chain-enhancer (NF-κB) of activated B cells signaling pathway, inducing mitochondrial apoptosis, and suppressing angiogenesis and bone destruction within the tumor microenvironment. However, the autophagic process activated by the accumulation of intracellular misfolded immunoglobulins leads to bortezomib resistance in multiple myeloma (Cengiz Seval and Beksac, 2018).

MM cells exhibit higher intracellular iron and ferritin levels compared to normal cells. Bortezomib can trigger ferritin degradation, increase intracellular free Fe²⁺, and promote ferroptosis in MM cells. Further mechanistic studies have shown that bortezomib effectively increases the level of NCOA4 by preventing proteasomal degradation, confirming its role in enhancing ferritinophagy. Moreover, the combined use of bortezomib and the ferroptosis inducer RSL - 3 can synergistically promote ferroptosis in MM cell lines. The synergistic effect of bortezomib and RSL - 3 in MM cells can be successfully counteracted by using the ferroptosis inhibitor liproxstatin - 1 (Zhang et al., 2024f).

Treatment with docosahexaenoic acid or eicosapentaenoic acid (DHA/EPA) can enhance the sensitivity of MM cells to bortezomib. Compared with the combined treatment of DHA/EPA and bortezomib, the sole application of DHA/EPA can significantly reduce the intracellular GSH level and alter the expression of metabolites and key enzymes related to GSH metabolism. RNA - seq indicates that DHA/EPA may enhance the efficacy of bortezomib by activating ferroptosis - related signaling pathways, suggesting that ferroptosis may play a positive role in improving drug sensitivity and overcoming drug resistance in the treatment of MM (Chen J. et al., 2021).

In conclusion, ferroptosis - related genes may become important factors for MM prognosis assessment, and more relevant genes still need to be explored through experiments. Although the above evidence proves the important role of ferroptosis in MM, further research is still needed to determine the ferroptosis inducers applicable in the human body, as well as their concentrations and application methods, in order to exploit the potential of ferroptosis as a new and generalizable clinical strategy.

Fingolimod (FTY720) was initially used as an immunosuppressant for the treatment of multiple sclerosis (Cengiz Seval and Beksac, 2018). Fingolimod exerts its therapeutic effects in multiple sclerosis by activating sphingosine-1-phosphate receptors (S1PRs) and inducing their internalization, thereby blocking lymphocyte egress from lymphoid tissues to the periphery. This reduces the infiltration of autoreactive T cells into the central nervous system, ultimately attenuating inflammatory damage and slowing disease progression (Kappos et al., 2010). However, subsequent studies have revealed its extensive anti - tumor effects (Hasan Ali et al., 2020). Research has shown that FTY720 can reduce the mRNA and protein levels of GPX4 and SLC7A11 in MM cells. As key regulators of ferroptosis, GPX4 and SLC7A11 are highly expressed in MM cells, indicating that the induction of MM cell death by FTY720 is likely related to the ferroptosis pathway. Further studies have demonstrated that FTY720 activates PP2A to dephosphorylate the AMP - activated protein kinase subunit α (AMPKα) and reduces the expression of phosphorylated eukaryotic elongation factor 2 (eEF2), ultimately leading to MM cell death. FTY720 induces ferroptosis and autophagy through the PP2A/AMPK signaling pathway, and these two modes of cell death can promote each other, providing a new strategy for the treatment of MM (Zhong et al., 2020).

Adapalene (ADA), a third-generation retinoid, is commonly used for the treatment of acne vulgaris. ADA selectively activates retinoic acid receptors (RAR-β/γ), thereby inhibiting excessive proliferation and differentiation of keratinocytes, reducing follicular hyperkeratinization, and downregulating inflammatory cytokines such as IL-6, ultimately contributing to its therapeutic effects in acne (Waugh et al., 2004). Recent studies have shown that ADA induces dose-dependent cell death in MM cells (Cao et al., 2024). ADA induces ferroptosis in MM cells by downregulating the protein expression of GPX4 and SLC7A11, which are key ferroptosis marker proteins. Moreover, studies have found that ADA is beneficial in restoring the sensitivity of cells from patients with bortezomib - resistant relapsed or refractory MM to bortezomib. ADA can disrupt the activation of the NF-κB pathway triggered by bortezomib and promote cell death in the bortezomib - resistant MM subpopulation (Cao et al., 2024).

Zhang et al. investigated the effects of the novel methyltransferase G9a inhibitor DCG066 on MM cells. They found that after DCG066 intervention, the levels of ROS, iron, and MDA in MM cells increased significantly, while the level of GSH decreased. The protein expression levels of SLC7A11, GPX4, Nrf2, and HO - 1 were significantly reduced. These phenomena could be reversed by the ferroptosis inhibitor Ferrostatin-1 and the Nrf2 activator tert - butylhydroquinone, which confirmed that DCG066 can inhibit the proliferation of MM cells and induce ferroptosis through the Nrf2/HO - 1 signaling pathway (Zhang et al., 2024g).

Disulfiram (DSF) is an FDA-approved drug for the treatment of alcohol dependence. It exerts its effect by inhibiting aldehyde dehydrogenase (ALDH), thereby blocking the conversion of ethanol to acetic acid. This leads to the accumulation of acetaldehyde in the body, causing adverse reactions such as nausea, vomiting, and palpitations, which help establish an aversive response to alcohol consumption (Heather, 1989). In recent years, DSF has shown emerging therapeutic potential in hematological malignancies due to its low toxicity and multi-target properties (Weiser Drozdkova and Smesny Trtkova, 2021). Arkan et al. found that treatment with disulfiram (DSF) increased the production of cytoplasmic and mitochondrial ROS in MM cells, led to the loss of mitochondrial membrane potential and an increase in the level of lipid peroxidation, and caused a significant downregulation of ferroptosis - related genes including GPX4 (Arkan and Akcora-Yildiz, 2025). The ferroptosis inhibitor liproxstatin - 1 could alleviate DSF - induced ferroptosis in MM cells by promoting the upregulation of GPX4. DSF can also overcome carfilzomib resistance by increasing the level of lipid peroxidation and exert a synergistic effect with carfilzomib in carfilzomib - resistant MM cell lines, indicating the potential of DSF in the treatment of MM.

T-5224 is an activator protein-1 (AP-1) inhibitor that specifically blocks the DNA-binding activity of the c-Fos/c-Jun heterodimer, thereby suppressing the expression of downstream pro-inflammatory cytokines such as TNF-α and matrix metalloproteinases like MMP-3. Through this mechanism, T-5224 exerts anti-inflammatory, antioxidant, and anti-degenerative effects (Sasakura et al., 2024). Previous studies have shown that T - 5224 can inhibit the proliferation of MM cells and induce their apoptosis (Tang et al., 2023). Tang et al. found that T - 5224 - induced MM cell death could be reversed by the ferroptosis - specific inhibitor ferropstatin-1, and T - 5224 reduced the protein levels of GPX4 and SLC7A11, the key regulators of ferroptosis in MM cells. Further research revealed that T - 5224 reduced the phosphorylation of components in the PI3K and AKT signaling pathways, suggesting that T - 5224 may induce ferroptosis in MM cells by regulating the PI3K/AKT signaling pathway (Tang S. et al., 2024) (Table 3).

In another study, MM cells harboring the t (4; 14) translocation exhibited marked sensitivity to Class II ferroptosis inducers (Class II FINs), whereas t (4; 14)-negative cells were resistant. This selective cytotoxicity is attributed to the overexpression of MMSET, a histone methyltransferase upregulated due to the t (4; 14) translocation. MMSET enhances transcriptional activation of ACSL4, facilitating the incorporation of polyunsaturated fatty acids (PUFAs) into membrane phospholipids. PUFA enrichment increases oxidative damage susceptibility, thereby heightening ferroptosis sensitivity in t (4; 14)-positive MM cells.In vitro assays confirmed that combining Class II FINs with bortezomib results in enhanced ferroptosis induction and significantly reduced viability of t (4; 14)-positive MM cells. As a genetically guided therapeutic strategy, this approach holds great clinical promise. Moreover, MMSET and ACSL4 expression levels may serve as predictive biomarkers for Class II FIN responsiveness, providing a basis for patient stratification (Zhang J. et al., 2024).