SOX4 drives ferroptosis resistance of non-small cell lung cancer by regulating PI3K/AKT/SREBP1/SCD1 signaling axis

Abstract Non-small cell lung cancer (NSCLC) remains a challenging disease due to its high heterogeneity and the lack of effective treatment strategies. Ferroptosis, a recently identified form of regulated cell death driven by the accumulation of lipid hydroperoxides, has emerged as a promising therapeutic strategy in NSCLC. Whereas ferroptosis-based therapy also faces the challenge of resistance, hindering its further clinical translation. Thus, there is an urgent need to identify novel ferroptosis regulators and elucidate their mechanisms. In this study, we found that SRY-box transcription factor 4 (SOX4) is frequently overexpressed in NSCLC, and its elevated expression correlates with poor patient survival. Importantly, SOX4 overexpression conferred NSCLC cells resistance to ferroptosis inducer RSL3, whereas SOX4 knockdown enhanced cellular sensitivity to RSL3. Mechanistically, stearoyl-CoA desaturase 1 (SCD1) was identified as a key downstream effector of SOX4. SCD1 overexpression counteracted the pro-ferroptotic effects of SOX4 knockdown, whereas SCD1 silencing reversed the SOX4 overexpression-induced anti-ferroptotic phenotype. Furthermore, SOX4 promoted SCD1 expression by activating PI3K/AKT/SREBP1 signaling pathway. In summary, our results establish SOX4 as a critical regulator of ferroptosis and propose the SOX4–SCD1 axis as a candidate therapeutic target for inducing ferroptosis in NSCLC. These findings also provide new insights into the mechanistic link between SOX4 and SCD1 in cancer biology.