Cuproptosis and Mitophagy Mediated by the THUMPD1/IGF2R-Dependent Suppression of AKT and Activation of AMPK Signaling Suppress Lung Adenocarcinoma Progression

Lung adenocarcinoma (LUAD) remains a leading cause of cancer-related mortality. N4-acetylcytidine (ac4C) modification regulates mRNA stability and translation, but the role of its associated co-factor, THUMP domain-containing protein 1 (THUMPD1), in Cancer is unknown. Clinical LUAD samples and Gene Expression Omnibus (GEO) datasets were analyzed for THUMPD1 expression and prognosis. In vitro and in vivo functional assays were performed to assess the impact of THUMPD1 on LUAD. Multi-omics approaches and mechanistic studies were employed to identify downstream targets and signaling pathways. THUMPD1 was significantly downregulated in advanced-stage LUAD. THUMPD1 acted as a tumor suppressor, inhibiting LUAD cell proliferation, metastasis, and tumor growth in mouse models. Mechanistically, THUMPD1 directly bound to and upregulated the translation of insulin-like growth factor 2 receptor (IGF2R) mRNA in an ac4C-independent manner by facilitating its cytoplasmic localization. The THUMPD1-IGF2R axis inhibited Akt signaling, which in turn led to the activation of AMPK. This resulted in intracellular Cu⁺ accumulation, triggering Cuproptosis and excessive Mitophagy, ultimately suppressing tumor growth. Therapeutically, the copper ionophore elesclomol potently inhibited tumor growth in a Thumpd1-knockout mouse model of LUAD.