Emerging metabolic alterations associated with cancer cell survival and proliferation

Metabolic adaptations, primarily characterized in the context of oxidative phosphorylation and aerobic glycolysis, optimize biosynthesis of energy sources and cellular building blocks to support cell proliferation. Paracrine secretion of lactate, certain amino acids, e.g., glutamine, and lipids, e.g., fatty acids, have also been shown to be utilized as alternative sources of ‘fuel’ (Hanahan, 2026).

While less characterized, emerging evidence also implicates biophysical properties of metabolites for maintenance and clearance of intracellular organelles, particularly mitochondria, to support cancer survival and proliferation. To this end, using spatial metabolite imaging, Chen and colleagues identified long-chain hydroxylated sulfatides to be selectively enriched in neoplastic epithelium of intraductal papillary mucinous neoplasms (IPMN), established precursor lesions to pancreatic ductal adenocarcinoma (PDAC) (Chen et al., 2025). Through spatial transcriptomics, the authors further showed cognate transcripts involved in sulfatide metabolism, including ceramide galactosyltransferase (also known as UGT8) and galactose-3-O-sulfotransferase 1 (GAL3ST1), to co-localize with areas of sulfatide enrichment. Mechanistically, sulfatide biosynthesis was linked to maintenance of mitochondrial morphology and function. Genetic or pharmacological suppression of UGT8 resulted in mitochondrial enlargement, loss of mitochondrial respiration, and increased susceptibility to intrinsic apoptosis (Chen et al., 2025). These findings insinuate a biophysical role of sulfatide in maintaining cancer-cell associated mitochondrial function, which may have broad relevance to other cancer types (Yoda et al., 1979; Morichika et al., 1996; Makhlouf et al., 2004).

Vykoukal and colleagues reported that enhanced scavenging of sphingomyelin by cancer cells, which they detailed in the context of triple negative breast cancer, is a ready source of ceramides for glycosphingolipid biosynthesis that supports extracellular vesicle (EV)-mediated clearance of damaged mitochondria as an alternative complementary mechanism to mitophagy. Glucosylceramide synthase (UGCG) was identified as a key mediator of this onco-metabolic process. Small molecule targeting of UGCG via repurposing of eliglustat resulted in ceramide-mediated mitophagy and subsequent cell death in vitro and markedly attenuated tumor development in vivo (Vykoukal et al., 2025). Similar findings have also been reported in prostate cancer (Vykoukal et al., 2020). These findings provide compelling evidence linking glycosphingolipid metabolism to regulation of mitochondrial dynamics, with potential therapeutic benefit.