Hypoxia-triggered autophagy modulates cisplatin resistance in non-small cell lung Cancer via EIF2AK3-dependent PI3K/AKT signaling and mTOR-independent mechanisms.

Chemoresistance in non-small-cell lung cancer (NSCLC) remains a significant clinical challenge, often exacerbated by the tumor microenvironment's hypoxic conditions. Hypoxia has been implicated in promoting autophagy and contributing to chemoresistance, yet the underlying mechanisms are not fully elucidated. In this study, we investigated the role of EIF2AK3 in hypoxia-induced autophagy and cisplatin (DDP) resistance in NSCLC cells. Our findings demonstrated that hypoxia upregulates EIF2AK3 expression, leading to enhanced autophagy, as indicated by increased LC3-II/I ratios. Pharmacological inhibition of autophagy with 3-MA effectively reversed hypoxia-induced DDP resistance. Mechanistically, hypoxia-activated EIF2AK3 enhanced autophagy and decreased DDP sensitivity in NSCLC cells via PI3K/AKT signaling, independent of mTOR activity. Activation of autophagy by rapamycin counteracted the effects of EIF2AK3 knockdown on both autophagy and PI3K/AKT signaling. Consistently, EIF2AK3 silencing in xenograft models enhanced the therapeutic efficacy of DDP by suppressing autophagy and attenuating PI3K/AKT activation. Collectively, our findings indicate that EIF2AK3 is a critical regulator of hypoxia-triggered autophagy in NSCLC, and targeting EIF2AK3-mediated PI3K/AKT signaling may represent a promising strategy to overcome cisplatin resistance.