Succinate dehydrogenase expression and activity: A potential molecular fingerprint with metabolism-rewiring properties and clinical impact in undifferentiated pleomorphic sarcomas

Undifferentiated pleomorphic sarcoma (UPS) remains one of the most clinically aggressive and poorly characterized soft tissue sarcoma (STS) subtypes. To uncover distinctive molecular traits for UPS, a multi-omics analysis of UPS compared to leiomyosarcoma (LMS), and liposarcoma (LPS) was performed. Transcriptomic profiling revealed that UPS exhibits overexpression of genes encoding succinate dehydrogenase (SDH) subunits, particularly SDHB, SDHC, and SDHD, distinguishing it from LMS and dedifferentiated LPS (DDLPS). This finding was validated using the TCGA-SARC dataset. High SDHB expression in UPS was significantly associated with shorter overall survival (OS) and shorter OS from the date of first metastasis. Immunohistochemistry validated elevated SDHB protein levels in UPS and LMS relative to DDLPS. Despite overexpression of SDH subunits, metabolomic profiling demonstrated a significantly higher succinate-to-fumarate ratio in UPS, suggesting functional impairment of SDH enzymatic activity potentially due to post-translational modifications, altered assembly of SDH subunits, or imbalanced tricarboxylic acid (TCA) flux. This paradoxical phenotype of SDH overexpression with enzymatic dysfunction defines a unique molecular and metabolic subtype of UPS with prognostic significance. Recognition of this distinct SDH- associated molecular and metabolic phenotype provides insight into UPS pathogenesis, identifies a potential novel prognostic biomarker, and suggests a new avenue for metabolic-targeted therapy.