CISD1 (CDGSH Iron Sulfur Domain 1)

In an orthotopic TNBC mouse model, xanthatin significantly suppressed tumor growth without causing systemic toxicity. Collectively, our findings provide the first demonstration that xanthatin directly targets CISD1 at the Trp-75 site to trigger ferroptosis and mitophagy, highlighting its promise as a therapeutic candidate for TNBC.

These findings indicate that ferroptosis dysregulation is a hallmark of aggressive UM. SLC7A11, GPX4, and TFR1 represent clinically relevant biomarkers and potential therapeutic targets.

Here, we present a scalable gram-level synthesis of the thiazolidinedione (TZD) containing NL-1 from the precursor CI-987 using the Hantzsch ester reduction as an alternative to conventional lithium borohydride or cobalt chloride-based methods. This optimized protocol enables the reliable production of NL-1 in quantities sufficient for preclinical disease modeling.

Notably, CISD1 expression is significantly correlated with tumor stemness indices, tumor mutation burden, microsatellite instability, and immune checkpoint proteins in multiple cancers, and altered CISD1 levels are also observed in patients responding to immunotherapy, further supporting its role not only in prognosis but also as a key predictor in immunotherapy responses and outcomes. Our findings demonstrate CISD1 as a reliable and promising diagnostic, prognostic, and immunotherapeutic biomarker for multiple cancers, emphasizing its crucial role in cancer biology and potential to guide personalized cancer therapies.

This study is the first to demonstrate the critical role of the EC tumor microbiome and its metabolite butyrate in modulating progesterone response in FPT. Our findings provide a new mechanistic insight and offer a strong rationale for targeting the microbiota-ferroptosis axis to overcome progesterone resistance in EC patients.

Moreover, RNA deep sequencing indicated that SB-T-101141 synergistically enhanced the iron-dependent activation of JNK and PERK pathways via KHSRP. Altogether, our results here demonstrate the potential clinical application of SB-T-101141 as a novel ferroptosis inducer in Paclitaxel-resistant breast cancer treatment.

Furthermore, CISD1 has potential applications in immunotherapy. These findings may provide novel theoretical insights into the treatment of LUAD.

We further reveal that a peptide derived from the same domain of the human CISD1 (mitoNEET; mNT19-42) protein, a close family member to CISD2, has no killing activity towards cancer cells, and that dimers of NAF-144-67 (at two different orientations) have higher anticancer activity compared to monomeric NAF-144-67. Our findings shed new light on the biological activity of NAF-144-67 and bring it closer to becoming a potential new anticancer drug.

We further reveal that a peptide derived from the same domain of the human CISD1 (mitoNEET; mNT 19-42 ) protein, a close family member to CISD2, has no killing activity towards cancer cells, and that dimers of NAF-1 44-67 (at two different orientations) have higher anticancer activity compared to monomeric NAF-1 44-67 . Our findings shed new light on the biological activity of NAF-1 44-67 and bring it closer to becoming a potential new anticancer drug.

Our findings demonstrate that GCN5L1/CISD1 axis is crucial for sorafenib resistance and would be a potential therapeutic strategy for sorafenib resistant HCC.

In conclusion, our study revealed that targeting CISD1 with NL-1 reduced reactive oxygen species accumulation, mitochondrial dysfunction, and apoptosis via the PI3K and MAPK pathways in HEI-OC1 cell lines and mouse cochlear explants in vitro, and it protected against CIHL in adult C57 mice. Our study suggests that CISD1 may serve as a novel target for the prevention of CIHL.

IHC analysis also demonstrated that a high expression of HSPA5 in patients with metastatic LSCC in the study cohort was associated with shorter PFS and overall survival. In conclusion, the present study demonstrated that the expression of the ferroptosis-related gene HSPA5 may be a negative prognostic marker for LSCC.