TMEM72 Inhibits the proliferation by promoting cellular senescence through the activation of the P38/MAPK signaling pathway in renal cell carcinoma

Background: Renal cell carcinoma (RCC) is a highly heterogeneous malignancy lacking reliable prognostic biomarkers and effective therapeutic targets. TMEM72, a kidney-enriched protein, is dysregulated in RCC, yet its biological function and underlying mechanisms remain unclear. Methods: Proteomic profiling of paired RCC and adjacent tissues was performed to identify differentially expressed proteins. TMEM72 expression and clinical relevance were validated using the TCGA-KIRC cohort and an independent patient cohort. Functional assays, including proliferation, cell cycle, and senescence analyses, were conducted in gain- and loss-of-function RCC models, and in vivo effects were evaluated using a xenograft model. RNA sequencing, single-cell analysis, and immune infiltration analysis were performed to explore underlying mechanisms. Results: TMEM72 was significantly downregulated in RCC and its low expression was associated with poor prognosis. TMEM72 overexpression suppressed RCC cell proliferation and tumor growth, whereas its silencing promoted tumor progression. Mechanistically, TMEM72 induced G1/S cell cycle arrest and promoted cellular senescence. Further analyses revealed that TMEM72 activated the p38/MAPK signaling pathway, leading to enhanced phosphorylation of p38 and p53, while pharmacological inhibition of p38 partially reversed these effects. Immune microenvironment analysis showed that TMEM72 was predominantly expressed in epithelial and malignant cells and was positively associated with infiltration of anti-tumor immune cells, including M1 macrophages, monocytes, and NK cells, but negatively correlated with immunosuppressive populations such as regulatory T cells and M0 macrophages. Conclusions: TMEM72 suppresses RCC progression by promoting p38/MAPK-dependent cellular senescence and may contribute to tumor immune microenvironment remodeling, highlighting its potential as a prognostic biomarker and therapeutic target.