RSL3

Notably, pitavastatin calcium synergized with the ferroptosis inducer RSL3 to enhance ferroptotic activity and suppress HNSCC progression. These findings delineate a TRAPPC4-FOS-TRIM55-GPX4 signaling axis that drives ferroptosis resistance and tumor progression and highlight TRAPPC4 as a promising therapeutic target for ferroptosis-based intervention in HNSCC.

Lipophagy can promote RAS-selective lethal 3 (RSL3)-induced ferroptosis. LAPTM5 enhanced the sensitivity of glioma cells to ferroptosis inducer erastin, while suppression of lipophagy inhibited LAPTM5-mediated sensitization to erastin. The finding that glioma cells with high LAPTM5 expression were more sensitive to ferroptosis inducers suggests that glioma patients with high LAPTM5 expression may be more responsive to ferroptosis-inducing therapies.

Moreover, NheA-O activity synergizes with RSL3, and NheA-O mediated cell death is antagonized by Fer-1, indicating the role of NheA-O in inducing ferroptosis-like cell death. Overall, these results describe NheA-O as a novel therapeutic agent to combat tumorigenesis by targeting tumor cell membrane and proteasomal degradation of GPX4 to trigger ferroptosis-like cell death and expands the paradigm of tumoricidal protein-lipid complexes functionality across biological kingdoms.

Interestingly, chemotherapy-resistant cancer cells can be induced to undergo ferroptosis, prompting our investigation into RSL3, a potent ferroptosis inducer, in MSS CRC cells...Notably, the combination enhanced the antitumor response of anti-PD1, a treatment otherwise ineffective on this tumor. These findings suggest that targeting HIF-1α represents a promising therapeutic strategy when used in conjunction with a ferroptosis inducer for the treatment of MSS CRC.

Ferroptosis induction by RSL3/FIN56 led to increased TFR1 expression and ROS generation...Temozolomide in combination with siRNA-mediated gene silencing showed a significantly higher antitumor effect than the drug or silencing alone. This may be one of the important therapeutic vulnerabilities of GBM. High TFR1 expression was associated with shorter overall survival in all gliomas together but not in GBM separately.

RRM2 inhibited ferroptosis by regulating the HIF-1α signalling pathway, thereby promoting the progression of ICC. The RRM2/HIF-1α/ferroptosis axis may become a potential target for ICC therapy.

TRIM31 promotes ESCC progression by degrading VDAC1 and suppressing ferroptosis. Targeting TRIM31 enhances ferroptosis-based therapy and represents a novel, clinically actionable strategy for ESCC treatment. Antioxid. Redox Signal. 44, 550-571.

We also demonstrated that chemical inhibition of these proteins using RSL3 (GPX4 inhibitor) and erastin (xCT inhibitor) significantly suppressed osteosarcoma cell growth. Collectively, our findings reveal that GPX4 inhibition initiates ferroptosis while simultaneously activating NRF2-driven antioxidant defenses, iron homeostasis mechanisms, and adaptive cell survival signaling. The results highlight potential therapeutic strategies that combine GPX4 inhibition with targeted disruption of compensatory pathways to overcome ferroptosis resistance in osteosarcoma.

The AR antagonist enzalutamide sensitises AR expressing melanoma cells to RSL3 and erastin independent of phenotype state, but in FAOhigh BRAFi relapsed tumours AR up-regulation correlates with the undifferentiated/neural-crest like (UD/NC) state, and enzalutamide synergises with ranolazine in ferroptosis-induction in UD/NC cells. Thus, therapeutically combining ranolazine with the AR inhibitor enzalutamide to induce ferroptosis can circumvent dedifferentiation related BRAFi resistance and could increase therapeutic activity and long-term efficacy.

FAT4 may enhance ferroptosis sensitivity in HCC by suppressing GPX4 and SLC7A11 expression, potentially by inhibiting PI3K/AKT signaling. Thus, this study presents FAT4 as a biomarker associated with tumor progression and a potential determinant for overcoming ferroptosis resistance in HCC.

Selenoenzyme glutathione peroxidase 4 (GPX4) controls this process by reducing lipid peroxides and can be pharmacologically inhibited by agents such as RSL3 and JKE1674...However, by assessing expression of iron regulatory genes as well as employing two orthogonal approaches to measure labile iron, we found that the LIP did not measurably increase during ferroptosis induction with GPX4 or SLC7A11 inhibition. These findings suggest that the LIP does not expand upon pharmacologically initiated ferroptosis, despite the potentiating effect of exogenous iron supplementation.

Gomisin B inhibited the transcriptional activation of USP7 by downregulating ESR1, thereby suppressing the deubiquitination of SREBF1. This enhanced NB ferroptosis to alleviate NB progression.