LSMEM1 as a prognostic biomarker in renal cell carcinoma through PKA/PPAR-α pathway activation

Leucine Rich Repeat and Sterile Alpha Motif Containing 1 (LSMEM1) has not been well characterized in renal cell carcinoma (RCC). This study aimed to elucidate the clinicopathological significance and functional role of LSMEM1 in RCC and to determine whether its effects are mediated through the cAMP/PKA-PPAR-α signaling axis. Analysis of TCGA RCC cohorts revealed that LSMEM1 expression was significantly upregulated in RCC and correlated with advanced tumor stage, higher histological grade, and poorer patient survival. Gain- and loss-of-function experiments in A498 and ACHN demonstrated that LSMEM1 enhanced cell proliferation, migration, and invasion, accompanied by increased protein kinase A (PKA) phosphorylation and neutral lipid accumulation. LSMEM1 overexpression promoted tumor growth in xenograft models, whereas pharmacological inhibition of PPAR-α using GW6471 markedly reduced LSMEM1-associated neutral lipid accumulation and preferentially suppressed the growth of LSMEM1-overexpressing tumors. Pathway enrichment analyses further supported the involvement of lipid metabolic signaling downstream of LSMEM1. Collectively, these findings suggest that LSMEM1 promotes RCC progression at least partially through activation of the PKA/PPAR-α axis and may serve as a prognostic biomarker, while identifying PPAR-α as a functionally relevant downstream mediator.