biostudies-literatureCal KU.S. Department of Health & Human Services | National Institutes of Health (NIH)U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)American Heart Association (American Heart Association, Inc.)1550-1569https://www.ebi.ac.uk/biostudies/studies/S-EPMC12373507biostudies-literatureUnknown7(8)The emergence of glucagon-like peptide-1 agonists represents a notable advancement in the pharmacological treatment of obesity, yet complementary approaches are essential. Through phenotypic drug discovery, we developed promising nitroalkene-containing small molecules for obesity-related metabolic dysfunctions. Here, we present SANA, a nitroalkene derivative of salicylate, demonstrating notable efficacy in preclinical models of diet-induced obesity. SANA reduces liver steatosis and insulin resistance by enhancing mitochondrial respiration and increasing creatine-dependent energy expenditure in adipose tissue, functioning effectively in thermoneutral conditions and independently of uncoupling protein 1 and AMPK activity. Finally, we conducted a randomized, double-blind, placebo-controlled pNature metabolismA nitroalkene derivative of salicylate, SANA, induces creatine-dependent thermogenesis and promotes weight loss.PMC12373507R01 HL-128485R01DK124510-01R01HL153532NS AI144004R35GM11952819TPA34850089R01 HL-168290NS 112727Cal KDeVallance ERuiz SHaag JAgorrody GGiri SBenitez-Rosendo ALai de Souza LOPeclat TRDapueto RVerdes JMMoyna GContreras PWang YPerez-Torrado VLeyva AHollander JMBreining PIngold MAlves JMde la Sovera VVilaseca CWhite TAQuijano CHandy RMEspasandin CGalliussi GRadi RRodriguez-Duarte JAicardo AO'Doherty RLeonardi RKamaid ADu JMori MAGarat MPBresque MLopez GVVendelbo MHColella LDuran REscande CKelley EEChini ENSantos LZiegler LCalliari AValez VMeadows EFestuccia WTFranca JVHolloway GPLeiria LOLopez ASantana Barbosa GCKing RThompson KLLino CAPorcal WCamacho-Pereira JChichierchio MSRattan RLewis SEJakobsen SVieira TSMenezes Dos Reis LBatthyany CMoraes-Vieira PfalseA nitroalkene derivative of salicylate, SANA, induces creatine-dependent thermogenesis and promotes weight loss.The emergence of glucagon-like peptide-1 agonists represents a notable advancement in the pharmacological treatment of obesity, yet complementary approaches are essential. Through phenotypic drug discovery, we developed promising nitroalkene-containing small molecules for obesity-related metabolic dysfunctions. Here, we present SANA, a nitroalkene derivative of salicylate, demonstrating notable efficacy in preclinical models of diet-induced obesity. SANA reduces liver steatosis and insulin resistance by enhancing mitochondrial respiration and increasing creatine-dependent energy expenditure in adipose tissue, functioning effectively in thermoneutral conditions and independently of uncoupling protein 1 and AMPK activity. Finally, we conducted a randomized, double-blind, placebo-controlled p2025-01-01T00:00:00Z2025 Aug2026-05-09T10:43:46.075Z2026-04-08T00:47:57.123ZS-EPMC123735074052792410.1038/s42255-025-01311-z