This study found that HSF4 overexpression markedly attenuated Erastin-induced cell death and mitochondrial damage in HT29 and HCT116 cells...In vivo experiments, MBOAT1/2 knockdown effectively reduced tumor volume and downregulated the number of Ki-67-positive cells, GPX4, and SLC7A11, while upregulating ACSL4. In conclusion, HSF4 alleviates ferroptosis in CRC cells and facilitates tumor progression by upregulating MBOAT1/2 transcription, thereby limiting lipid peroxidation and Fe2+ accumulation.

Strikingly, subtherapeutic doses of rottlerin enhanced the efficacy of clinical ferroptosis inducers (RSL3 and sorafenib), and this chemosensitization effect persisted in PKCδ-depleted models, indicating a target-agnostic mechanism. Our work provides the first demonstration of rottlerin's ferroptotic activity in HCC, positioning it as a dual degrader capable of overcoming compensatory antioxidant adaptations. These findings advocate for rottlerin's clinical development either as monotherapy or in rational combinations to augment ferroptosis-targeted HCC treatment.

In addition, the ferroptosis inducers erastin and RSL3 are capable of enhancing the efficacy of traditional therapies and seeking solutions for the chemoresistance problem. The hurdles to be overcome are finding reliable biomarkers for the prediction of ferroptosis sensitivity and designing targeted delivery systems for minimal off-target effects. Clinically, these techniques offer novel concepts in the treatment of CCA, making further research key to these conclusions being adopted in practice.

Using CRISPR/Cas9-mediated knockout and rescue experiments in EOC cell lines, we demonstrate that MED12 deficiency significantly enhances sensitivity to ferroptosis inducers (RSL3 and Erastin), as evidenced by reduced IC50 values...Pharmacological inhibition of YAP with verteporfin or siRNA-mediated TEAD1 knockdown reverses ferroptosis sensitivity in MED12-deficient cells, confirming pathway specificity. These findings establish MED12 as a modulator of the YAP-TEAD1-ferroptosis axis and suggest that targeting this pathway could overcome chemoresistance in MED12-deficient EOC. Our work provides a mechanistic foundation for exploiting ferroptosis induction as a therapeutic strategy in ovarian cancer.

These findings demonstrate that mitochondrial COX4-1 rewires redox metabolism and diverts cell-death signaling away from ferroptosis toward apoptosis. Our results identify isoform-specific mitochondrial composition as a previously unrecognized determinant of regulated cell death and highlight COX4-1-driven mitochondrial remodeling as a potential mechanism of therapeutic resistance in glioblastoma.

Here, ERM proteins are identified as modulators of erastin-induced ferroptosis...Notably, other pro-oxidants similarly attenuate ferroptosis at appropriate concentrations. Together, these results establish ERM proteins as regulators of ferroptosis and reveal an underappreciated group of ferroptosis inhibitors that engage ROS-NRF2-mediated redox-adaptation.

Ferroptosis inducers have dual effects in NSCLC, namely, promoting tumor cell death and triggering PD-L1-dependent immune evasion via the PI3K-AKT-HIF-1α pathway. However, combining ferroptosis inducers with anti-PD-1 antibodies retains the anti-tumor effect of ferroptosis and overcomes immune evasion by obstructing the PD-L1 pathway, offering a novel strategy for enhancing NSCLC immunotherapy efficacy.

In MO3.13 cells, α-synuclein enhanced erastin-induced GPX4 loss, increased labile Fe2+ accumulation and aggravated mitochondrial depolarisation...Furthermore, the parallel reduction of circulating ODFC-EVs offers a readily accessible blood-based biomarker to discriminate MSA from PD. Together, these findings position the α-synuclein-NCOA4-FTH1 axis as a central pathogenic pathway and a compelling therapeutic target for MSA.

TRAF6 inhibition increased lipid peroxidation, mitochondrial reactive oxygen species (ROS), and Fe2+ accumulation, thereby exacerbating mitochondrial damage and enhancing RAS-selective lethal 3 (RSL3)-induced ferroptosis...PGG bind and degraded TRAF6 efficiently, triggering mitochondrial ferroptosis and robustly suppressing the growth of KRAS-mutant lung cancer, with partial rescue by ferroptosis blockade. These findings uncovered a previously unrecognized TRAF6/AKT-mediated mitochondrial ferroptosis axis and highlighted PGG as a promising candidate against KRAS-mutant lung cancer.

Overexpression of hsa-miR-520a-3p in NCI-H226 and NCI-H2170 cells increased lipid peroxidation (MDA increased), reduced intracellular GSH, and enhanced RSL3-induced cytotoxicity, indicative of ferroptosis activation. Conversely, MYO19 knockdown elevated ACSL4 and reduced SLC7A11, changes that were partially reversed by MYO19 re-expression. These findings suggest that the hsa-miR-520a-3p/MYO19 axis is associated with ferroptosis susceptibility and may influence the immunosuppressive tumor microenvironment.

Notably, by incorporation of a therapeutic payload (ML210), NV-TACs simultaneously exhibited targeted protein degradation and ML210-mediated ferroptosis through payload delivery capacity. Both in anti-PD-1-responsive and -resistant tumor models, NV-TACs demonstrated significant therapeutic efficacy without obvious systemic toxicity. The platform of NV-TACs paves new avenues for developing linker-free, modular, and bioinspired targeted protein degradation platforms.

These findings may explain one of the reasons for the suboptimal efficacy of simvastatin in the treatment of pancreatic cancer, while also providing new insights for research on the antitumor effects of statins.