Fatty acid‑activated proton transporter SR4 prevents hepatic steatosis and metabolic alterations in diabetic mice by improving mitochondria function, energy balance and oxidative stress

Type 2 diabetes (T2D) is a growing global health crisis, largely driven by rising obesity rates. Untreated T2D leads to severe complications such as cardiovascular disease, nephropathy, retinopathy, neuropathy and hepatic dysfunction. Current therapies primarily manage hyperglycemia but often fail to address core pathophysiological drivers such as insulin resistance and obesity. This highlights an urgent need for novel therapeutics with distinct mechanisms, particularly those targeting energy metabolism and insulin sensitivity, to improve long‑term T2D outcomes. Modulating mitochondrial respiration through mild uncoupling has emerged as a promising strategy to promote negative energy balance. SR4, a small‑molecule mitochondrial uncoupler, represents a novel class of fatty acid‑activated proton transporters. In the present study, the metabolic effects of oral SR4 administration were investigated in male db/db mice, a model of T2D. SR4 significantly reduced body weight gain and improved body composition by selectively decreasing fat mass without affecting lean mass. Indirect calorimetry demonstrated that SR4 treatment increased oxygen consumption and total energy expenditure, independent of food intake. Importantly, SR4 notably improved glycemic control, reduced insulin resistance and prevented dyslipidemia, hepatic steatosis and liver injury. Mechanistically, SR4 activated hepatic AMPK, enhanced mitochondrial respiration and mitigated oxidative stress. Liver transcriptomic profiling further demonstrated broad metabolic reprogramming, including downregulation of lipogenesis and PPARγ signaling, concurrently with the upregulation of genes involved in energy metabolism and antioxidant defense. Collectively, these findings demonstrated that SR4 ameliorates multiple aspects of metabolic dysfunction in an obese T2D mouse model by targeting key pathways in energy regulation and lipid metabolism. The present results provided additional mechanistic insights into the effects of mitochondrial uncouplers in the liver and support further investigation of SR4 and related fatty acid anion transporters as a novel therapeutic class for metabolic diseases.