CHAC1 (ChaC Glutathione Specific Gamma-Glutamylcyclotransferase 1)

Erastin (ER), a small-molecule compound, induces ferroptosis through ROS accumulation...Our findings highlight ASNS, CHAC1, PCK2, DDIT4, and ATF3/4 as potential biomarkers for ferroptosis in CRC. Monitoring the expression of these genes may help identify patients who are responsive to ferroptosis inducers and facilitate the development of personalized treatment strategies.

Furthermore, we examine the opposing roles of CHAC1 and CHAC2 in stem cell fate decisions via NOTCH1 signaling and development. The complex duality of CHAC1 in oncology, acting as both a tumor suppressor by promoting ferroptosis and a potential oncogene in TP53-mutant backgrounds, alongside its functions in neuroprotection and immunity, underscores its therapeutic potential.

Collectively, our data suggest that erianin serves as an inhibitor of vasculogenic mimicry. Our results unveil a novel therapeutic strategy for combating malignant progression by fine-tuning m5C modification with a natural product.

Finally, NOS2 knockdown using siRNA also showed enhanced expression of ferroptosis markers which is the same response observed with the treatment of the compounds. In conclusion, this study suggests that fungal endoperoxide-containing steroids from D. confragosa represent new ferroptosis inducers via targeting NOS2, supporting their potential as anticancer drug candidates.

To mimic ChaC1 overexpression by inducing endogenous ChaC1 high expression, a complementary ChaC1-induction-based screening was performed and revealed proteasome inhibitors (e.g., bortezomib, ixazomib, delanzomib) as potent inducers of endogenous ChaC1 via ATF4-dependent transcriptional activation. This functional convergence demonstrates that ChaC1 activation, either achieved through genetic manipulation or pharmacological induction, creates a synthetic lethal context for AUR in HCC cells. Together, our study establishes a ChaC1-based pharmacological discovery platform that identifies proteasome inhibitor and auranofin combination as a mechanistically rational anti-HCC strategy, providing both methodological innovation in drug repurposing screening and immediate translational potential for HCC treatment.

Additive suppression of inflammation was observed in NCM460 cells with combined CHAC1 knockdown and SQJZ treatment. SQJZ alleviates intestinal inflammation in CKD, potentially mediated by downregulation of CHAC1 and subsequent inactivation of the HIF-1 pathway, positioning SQJZ as a promising gut-targeted therapy in CKD.

Next, we have critically evaluated CHAC1-centered therapeutic approaches that primarily focused on tumor interventions, while discussing their implications for drug resistance and tumor suppression. Overall, interference with CHAC1 can induce programmed cell death across a spectrum of diseases, thereby providing novel opportunities for targeted therapy.

In the present study, Imatinib-sensitive K-562S cells were subjected to CBD treatment (IC50: 17.69 μM) for 4 and 12 h, followed by RNA sequencing to identify differentially expressed genes (DEGs)...The results presented in this study validate the considerable potential of CBD to induce broad transcriptional and signalling alterations, related to immune modulation, apoptosis, and metabolic processes in K-562S cells. These findings provide novel insights into the therapeutic potential of CBD and lay the groundwork for further investigation into its precision applications in haematological malignancies.

For prostate cancer, CHAC1 potentiates docetaxel cytotoxicity via coordinated induction of endoplasmic reticulum stress and ferroptosis, yet its suppression by cancer-associated fibroblast-derived exosomal miR-432-5p establishes therapy-reinforced chemoresistance...Notably, current evidence reveals no established link between CHAC1 and urothelial carcinoma pathogenesis. Further elucidation of CHAC1's mechanistic intricacies and therapeutic targeting (e.g., CHAC1 agonists, exosomal miRNA antagonists) may advance precision management of urological tumors.

iEV-150 integrates ANXA2-mediated miRNA loading, tumor-specific targeting, ferroptosis induction, and immune microenvironment reprogramming. This engineered EV strategy provides an effective RNA-based therapeutic platform to overcome ICB resistance and enhance precision treatment in melanoma.

Isochlorogenic acid A/C, apigenin, and chrysin were identified as key bioactive components. These findings lay the foundation for the development of natural ferroptosis-targeted drugs.