A small‑molecule HDAC/PDE modulator activates human adipocyte UCP1 and resolves inflammatory signaling

Obesity-associated inflammation in white adipose tissue (WAT) drives insulin resistance and type 2 diabetes. While UCP1-mediated thermogenesis is a therapeutic target, most browning agents lack anti-inflammatory activity. We aimed to identify small molecules that induce browning and suppress inflammation in human adipocytes. Human cohorts and cell line models were analyzed for inflammatory markers. We generated an in-house multicomponent reaction (MCR)-based chemical library and developed a proprietary high-throughput screening platform to identify UCP1 activators in human adipocytes. Lead compound CDC1011 was evaluated for effects on thermogenesis, mitochondrial respiration, glucose uptake, glycolysis, lipolysis, NF-κB signaling, cytokine secretion, and monocyte chemotaxis. Mechanistic studies assessed cyclic-nucleotide signaling, phosphodiesterase (PDE) inhibition, histone deacetylase (HDAC) modulation, and docking-based predictions. CDC1011 induced UCP1 expression and mitochondrial respiration, enhanced glucose uptake and lipolysis, and suppressed NF-κB activation, cytokine secretion, and monocyte recruitment. Mechanistically, CDC1011 elevated cAMP/PKA and cGMP signaling via PDE inhibition and attenuated HDAC activity, reprogramming adipocytes toward a thermogenic, anti-inflammatory phenotype. CDC1011 is a first-in-class small molecule with dual thermogenic and anti-inflammatory actions in human adipocytes, offering a promising pharmacological strategy for obesity-related metabolic disorders.