Molecular and cellular mechanisms of pentadecanoic acid

Pentadecanoic acid (C15:0) is an odd-chain fatty acid, the β-oxidation of which yields propionyl-CoA that replenishes succinyl-CoA and tricarboxylic acid cycle flux; higher circulating levels are associated with reduced type 2 diabetes, cardiovascular disease, metabolic dysfunction-associated steatotic liver disease, and mortality. Summarize the cellular and molecular mechanisms underlying these associations. A comprehensive literature search (2000-2025) identified studies of C15:0's mechanistic actions in vitro and in vivo, and multi-omics studies focused on receptor binding, signaling cascades, gene expression, and comparative pharmacology. C15:0 is a dual partial peroxisome proliferator-activated receptor α/δ agonist. It activates AMP-activated protein kinase, suppresses mechanistic target of rapamycin, and selectively inhibits histone deacetylase 6. It augments succinate-driven complex II respiration, preserves mitochondrial membrane potential, limits reactive oxygen species, and attenuates interleukin-6 (IL-6) - triggered Janus kinase 2/signal transducer and activator of transcription 3 and nuclear factor kappa B p65 signaling, lowering monocyte chemoattractant protein-1, tumor necrosis factor-alpha, and IL-6. Across the BioMAP^® human-primarycell platform - which tests 12 distinct primary human cell systems such as endothelial cells, fibroblasts, macrophages, and T-cells - C15:0 (17 µM) produced statistically significant changes in 36 mechanistically diverse biomarkers. This broad, multi-pathway modulation mirrors the phenotype produced by metformin and rapamycin, yet occurred with no detectable cytotoxicity, paralleling metformin and rapamycin with negligible cytotoxicity. C15:0 engages receptor targets that converge on enhanced lipid oxidation, cellular energetics, and inflammation resolution. Although prospective clinical outcomes are still lacking, the pleiotropic mechanism profile positions C15:0 as a potentially unique nutraceutical or adjunct therapeutic candidate. Further research is warranted to confirm its clinical impacts, optimize dosing, and clarify long-term safety as an essential fatty acid supporting metabolic and immune homeostasis.