CypA Mediates Non‐Small Cell Lung Cancer Chemoresistance by Attenuating Ferroptosis via Stabilizing SLC7A11

Abstract Non‐small cell lung cancer (NSCLC) remains a major oncological challenge due to intrinsic or acquired chemoresistance, underscoring the urgent need to decipher novel regulatory mechanisms. Here, cyclophilin A (CypA) is identified as a critical mediator of cisplatin (DDP)/paclitaxel (DTX) resistance in NSCLC by suppressing ferroptosis, an iron‐dependent form of regulated cell death. CypA is significantly overexpressed in DDP/DTX‐resistant NSCLC cell lines and patient tissues, correlating with poor prognosis. Mechanistically, CypA stabilizes the ferroptosis suppressor SLC7A11 by competitively binding to its K37 site, blocking ubiquitination and proteasomal degradation mediated by the E3 ligase TRIM3. This interaction maintains cystine uptake, glutathione biosynthesis, and redox homeostasis, thereby attenuating lipid peroxidation and ferroptosis induction by chemotherapeutics. knockout of CypA or pharmacological inhibition with cyclosporine A (CsA) reverse resistant NSCLC cells to DDP/DTX both in vitro and in vivo by restoring ferroptosis. Combined CsA and chemotherapy treatment significantly enhances tumor regression, as evidenced by increased 4‐HNE and reduced SLC7A11 expression in vivo. The study uncovers a CypA/SLC7A11/TRIM3 axis governing ferroptosis evasion in NSCLC chemoresistance and highlights CypA as a promising therapeutic target. Repurposing CsA to inhibit CypA represents a translatable strategy to overcome chemotherapy resistance, offering preclinical validation for improving outcomes in NSCLC patients.