BACKGROUND: Although transmembrane protein 106C (TMEM106C) has been elucidated to be overexpressed in cancers, its underlying mechanisms have not yet been fully understood. AIM: To investigate the expression levels and molecular mechanisms of TMEM106C across 34 different cancer types, including liver hepatocellular carcinoma (LIHC). METHODS: We analyzed TMEM106C expression patterns in pan-cancers using microenvironment cell populations counter to evaluate its association with the tumor microenvironment. Gene set enrichment analysis was conducted to identify molecular pathways related to TMEM106C. Chromatin immunoprecipitation followed by sequencing (ChIP-seq) analysis was conducted to identify upstream transcriptional regulators of TMEM106C. In LIHC, we examined mRNA profiles, performed in-house quantitative polymerase chain reaction, immunohistochemistry, and constructed a co-expression gene network. Functional assays, including cell counting kit-8, cell cycle, apoptosis, migration, and invasion, were conducted. The effect of nitidine chloride (NC) on LIHC xenograft was evaluated through RNA sequencing and molecular docking. Finally, potential therapeutic agents targeting TMEM106C were predicted. RESULTS: TMEM106C was significantly overexpressed in 27 different cancer types and presaged poor prognosis in four of these types, including LIHC. Across pan-cancers, TMEM106C was inversely correlated to the abundances of immune and stromal cells. Furthermore, TMEM106C was significantly linked to cell cycle and DNA replication pathways in pan-cancers. ChIP-seq analysis predicted CCCTC-binding factor as a pivotal transcriptional factor targeting the CONCLUSION: Overexpressed TMEM106C was predicted as an oncogene in pan-cancers, which may serve as a promising therapeutic target for various cancers, including LIHC. Targeting TMEM106C could potentially offer a novel direction in overcoming TKI resistance specifically in LIHC. Future research directions include in-depth experimental validation and exploration of TMEM106C's role in other cancer types.