Integrative multi-omics analysis identifies SMIM24 as a favorable prognostic biomarker in clear cell renal cell carcinoma

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Clear cell renal cell carcinoma (ccRCC) exhibits substantial molecular and clinical heterogeneity, contributing to variable disease progression and therapeutic outcomes. We previously identified a de-clear cell differentiation (DCCD) tumor state characterized by loss of canonical clear-cell features and aggressive clinical behavior. This study aimed to translate DCCD-associated biology into a prognostic framework and investigate its underlying molecular basis. Using TCGA-KIRC as the training cohort, we developed a five-gene prognostic signature comprising COL7A1, IGFN1, AJAP1, SMIM24, and ADGRV1, which consistently stratified patient survival across multiple public and institutional cohorts. Comparison with SSIGN, Leibovich, and ClearCode34-like models demonstrated that the DCCD signature provided complementary prognostic information. High-risk tumors exhibited enhanced proliferative and invasive programs, increased IL6-JAK-STAT3 pathway activity, and an immune-excluded microenvironment. Associations with treatment response were also observed in retrospective therapeutic cohorts. Integrated analyses of bulk and single-cell transcriptomics, spatial transcriptomics, tissue microarrays, CPTAC proteomics, and molecular interaction networks identified SMIM24 as an epithelial-associated factor linked to favorable outcomes and preserved metabolic programs. Functional experiments showed that SMIM24 overexpression suppressed migration, invasion, three-dimensional spheroid invasion, and clonogenic growth in ccRCC cells, accompanied by reduced JAK1 and STAT3 phosphorylation and decreased PD-L1 expression. Pharmacological activation of STAT3 with Colivelin partially restored PD-L1 expression in SMIM24-overexpressing cells. Collectively, these findings support the reproducibility of the DCCD-associated prognostic framework and identify SMIM24 as a candidate suppressor of ccRCC aggressiveness and PD-L1 expression, potentially acting in part through reduced STAT3 activation.

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