ACSL3 (Acyl-CoA Synthetase Long Chain Family Member 3)

These findings underscore ACSL3 as a significant biomarker and candidate therapeutic target in HCC. Its role bridges dysregulated lipid metabolism with oncogenic signaling and immune evasion, warranting further investigation into ACSL3-targeted strategies.

Our study introduced a novel prognostic tool that integrates ferroptosis and EMT-related biomarkers and offers valuable insights for developing personalized treatment strategies for ESCC patients.

Additionally, SLD regulated key signaling pathways including peroxisome proliferator-activated receptor(PPAR), tumor protein P53(P53), and Hippo. Further studies revealed that SLD activated the PPAR signaling pathway by upregulating key targets such as peroxisome proliferator-activated receptor δ(PPARδ) and fatty acid desaturase 2(FADS2) and downregulating Acyl-CoA synthetase long chain family member 3(ACSL3) and 3-hydroxy-3-methylglutaryl-CoA synthase 1(HMGCS1), which promoted fatty acid β-oxidation, inhibited fatty acid synthesis, improved hepatic lipid metabolism, and ultimately exerted the effects of protecting liver function and alleviating liver injury.

PCSK1N was progressively upregulated from normal prostate to castration-resistant disease and promoted proliferation, clonogenicity, migration and enzalutamide resistance, while its inhibition sensitized organoids and xenografts to AR-targeted therapy. These findings define a C4-centered lethal tumor axis and provide an explainable, experimentally supported framework for prognostic stratification in PCa.

Finally, we survey the evolving therapeutic landscape, encompassing small-molecule inducers, natural compounds, and innovative combination strategies designed to trigger ferroptosis. This comprehensive overview underscores ferroptosis as a critical vulnerability and a promising therapeutic target to overcome treatment resistance in RCC.

The present review seeks to fill this gap by summarizing recent advances in understanding the roles of the ACSL family across diverse diseases, with a focus on emerging therapeutic strategies that target these enzymes. This work provides critical insights that may inform future preclinical and clinical investigations of the ACSL family.

We analysed the clinical significance of TMEM166-regulated UPR in human HCC cells and noted that TMEM166 expression was negatively correlated with the activities of UPR-related transcriptional factors such as ATF4, ATF6 and XBP1s in the cells. This study is the first to elucidate the relationship among TMEM166, ER stress, and HCC and may provide and indicate newer avenues for TMEM166-targeted gene therapy strategies for HCC treatment.

Experiments both in vitro and in vivo showed that reducing ACSL3 levels significantly decreased liver cancer cell growth, indicating its potential as a therapeutic target. Our research underscores the promise of ACSL3 expression as a new biomarker for forecasting the outcomes of various human cancers and assessing the effectiveness of immunotherapy.

Our findings also demonstrated that the FDA-approved madecassic acid effectively mitigates vHC loss resulting from Gpx4 ablation and cisplatin administration through the modulation of Acsl3 and Gpx4. In summary, inhibiting ferroptosis may represent a potential strategy to protect against vestibular dysfunction caused by cisplatin-induced vestibulotoxicity.

Our results reveal a previously unrecognized role of AR in TAD pathogenesis and uncover the opposite yet complementary regulation of ACSL3/ACSL4 levels involved in lipid peroxidation-driven ferroptosis in VSMCs.

Molecular modeling and mutagenesis support its binding in the ACSL4 fatty acid pocket. The strong antiferroptotic activity of both compounds in cells, together with confirmed target engagement for 21, underscores the relevance of ACSL4 as a target for ferroptosis modulation.