Pan-cancer multi-omics analysis identifies TOMM22 as an oncogenic driver and therapeutic target in LIHC via ferroptosis regulation.

Mitochondrial dysfunction plays a pivotal role in tumor progression. TOMM22, a core receptor of the mitochondrial protein import complex, has been implicated in various cancers, though its pan-cancer roles remain insufficiently defined. This study aimed to explore the pan-cancer profile of TOMM22 and investigate its function in hepatocellular carcinoma (LIHC). We utilized multiple bioinformatics platforms to perform pan-cancer analyses of TOMM22 expression, prognostic value, mutations, and immune infiltration. Transcriptomic, single-cell, and spatial transcriptomic data from LIHC were used to validate TOMM22 expression and its clinical significance. In vitro experiments were conducted to examine its biological functions in LIHC cells. TOMM22 was significantly overexpressed in multiple cancer types, including LIHC, where it was associated with poor prognosis and high diagnostic value. Mutations in TOMM22 were linked to impaired survival outcomes, and its expression correlated with immune infiltration, cancer stemness, and mitochondrial function. In LIHC, TOMM22 upregulation was associated with advanced tumor grade and resistance to sorafenib. Knockdown of TOMM22 inhibited LIHC cell proliferation and induced ferroptosis by accumulating lipid reactive oxygen species (ROS) and promoting lipid peroxidation. This study provides comprehensive insights into the oncogenic role of TOMM22 across cancers, identifying it as a promising diagnostic biomarker and therapeutic target for the precision treatment of LIHC.