HMGCS2 serves as a potential biomarker for inhibition of renal clear cell carcinoma growth.

3-Hydroxymethylglutaryl-CoA synthase 2 (HMGCS2) is the rate-limiting enzyme for ketone body synthesis, and most current studies focus on mitochondrial maturation and metabolic reprogramming. The role of HMGCS2 was evaluated in a pan-cancer multi-database using R language, and HMGCS2 was lowly expressed or not differentially expressed in all tumor tissues compared with normal tissues. Correlation analysis of clinical case characteristics, genomic heterogeneity, tumor stemness, and overall survival revealed that HMGCS2 is closely related to clear cell renal cell carcinoma (KIRC). Single-cell sequencing data from normal human kidneys revealed that HMGCS2 is specifically expressed in proximal tubular cells of normal adults. In addition, HMGCS2 is associated with tumor immune infiltration and microenvironment, and KIRC patients with low expression of HMGCS2 have worse prognosis. Finally, the results of cell counting kit 8 assays, colony formation assays, flow cytometry, and Western blot analysis suggested that upregulation of HMGCS2 increased the expression of key tumor suppressor proteins, inhibited the proliferation of clear cell renal cell carcinoma cells and promoted cell apoptosis. In conclusion, HMGCS2 is abnormally expressed in pan-cancer, may play an important role in anti-tumor immunity, and is expected to be a potential tumor prognostic marker, especially in clear cell renal cell carcinoma.