Heme oxygenase-1 (HO-1) depletion promotes ferroptosis to reverse cisplatin-resistance via enhancing NCOA4-mediated ferritinophagy in ovarian cancer.

Ovarian cancer remains the deadliest gynecological malignancy, with cisplatin resistance being a major therapeutic challenge. This study investigates the role of heme oxygenase-1 (HO-1) in cisplatin resistance and its regulation mechanisms through ferroptosis and ferritinophagy. In this study, significant overexpression of HO-1 was observed in cisplatin-resistant ovarian cancer cells and tissues, correlating with poor patient prognosis. Using HO-1 inhibitors and siRNA-mediated knockdown, it was demonstrated that HO-1 depletion reversed cisplatin resistance by promoting ferroptosis, a form of iron-dependent cell death. Mechanistically, HO-1 knockdown increased nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy, resulting in elevated labile iron pool (LIP) levels, lipid peroxidation, and reduced glutathione (GSH) levels. Xenograft models further confirmed that HO-1 inhibition synergizes with cisplatin to suppress tumor growth by enhancing ferritinophagy-mediated ferroptosis. These findings highlight HO-1 as a key regulator of iron metabolism and ferroptosis in cisplatin-resistant ovarian cancer. In conclusion, our study demonstrates that HO-1 depletion enhances ferroptosis, reversing cisplatin resistance in ovarian cancer through NCOA4-mediated ferritinophagy. The combination of cisplatin with HO-1 inhibition emerges as a promising strategy to overcome cisplatin resistance, offering a potential therapeutic avenue for ovarian cancer treatment.