IL-17D promotes ferroptosis resistance in lung cancer via activating PPARγ pathway.

Despite significant advancements in targeted therapy and immunotherapy that have markedly improved the survival of patients with non-small cell lung cancer (NSCLC), challenges such as tumor heterogeneity and therapeutic resistance persist. Ferroptosis, a unique form of iron-dependent programmed cell death driven by lipid peroxidation, has emerged as a promising therapeutic target for cancer treatment. Interleukin-17D (IL-17D), a member of the IL-17 cytokine family, is involved in regulating immune cell responses within the tumor microenvironment. However, its role in ferroptosis remains unclear. In this study, we demonstrated that high IL-17D expression in lung cancer cell lines is significantly associated with ferroptosis resistance and predicts poor prognosis of patients with lung cancer. Mechanistically, IL17D overexpression promotes the expression of ferroptosis resistance-related genes by enhancing the accessibility of nuclear transcription factor Y (NFY) complex binding sites, and reduces intracellular lipid peroxidation levels. Notably, upon treatment with ferroptosis inducers, IL-17D significantly upregulates peroxisome proliferator-activated receptor gamma (PPARγ) expression, promotes cellular lipid droplet accumulation, and elevates ATP levels in lung cancer cells. Importantly, pharmacological inhibition of the PPARγ pathway reverses IL-17D-induced ferroptosis resistance. Collectively, these findings uncover a novel mechanism whereby IL-17D regulates ferroptosis through PPARγ-dependent lipid metabolic reprogramming, highlighting the IL-17D-PPARγ axis as a promising therapeutic target to overcome ferroptosis resistance in lung cancer.