KHSRP protects colorectal cancer cells against ferroptosis by regulating GPX4 expression through interaction with...

Ferroptosis is an iron-dependent form of programmed cell death driven by the accumulation of lipid peroxides. KHSRP, an RNA-binding protein, is known to orchestrate diverse cellular processes, including cell differentiation, proliferation, and lipid metabolism. However, its potential role in modulating ferroptosis in cancer remains unclear. In this study, we found that elevated KHSRP expression was associated with poor prognosis in colorectal cancer (CRC) patients. Knockdown of KHSRP significantly elevated lipid peroxidation, increased malondialdehyde (MDA) accumulation, and reduced glutathione (GSH) levels, ultimately triggering ferroptosis in CRC cells. Mechanistically, we discovered that KHSRP interacts with the splicing factor hnRNPM, which directly binds to GPX4 mRNA. Critically, hnRNPM overexpression effectively rescued the decrease in GPX4 expression and the ferroptotic phenotype induced by KHSRP knockdown. These results suggest that the KHSRP-hnRNPM complex binds to GPX4 mRNA and acts as a key regulator of its post-transcriptional fate to sustain GPX4 expression. Overall, our results uncover a novel regulatory mechanism whereby high KHSRP expression protects CRC cells from ferroptosis. Targeting the KHSRP-hnRNPM-GPX4 axis to overcome ferroptosis resistance represents a promising therapeutic strategy for CRC.