Niosomal Gallic Acid Attenuates Obesity-related Hepatic Steatosis Through Oxidative and Inflammatory Regulation With Associated Autophagy and Hedgehog Pathway Modulation.

Obesity is an epidemic condition that is linked to several health issues, including metabolic disorders, diabetes mellitus, and cardiovascular disease. The anti-inflammatory and antioxidant qualities of gallic acid (GA) are well-known. However, its low oral bioavailability limits its therapeutic potential. In this study, GA-Nio, a gallic acid-loaded niosome, was developed for potential anti-obesity and hepatoprotective effects. Forty male Wistar rats were utilized in this investigation. They were allocated into four groups: the first received a standard diet, the second received a standard diet plus GA-Nio, the third received an HFD, and the fourth received both an HFD and GA-Nio at a dose of 10 mg/kg body weight. The formulation showed a uniform size of 200.6 nm and a zeta potential of - 30 mV, suggesting good stability. GA-Nio administration reduced body weight, body mass index, adiposity index, liver weight, and fat accumulation. Additionally, GA-Nio lowered total cholesterol and triglycerides while increasing HDL levels, restored fasting glucose, insulin, and HOMA-IR, and regulated adipokines by increasing adiponectin and decreasing leptin. Mechanistically, the hepatoprotective effect was driven primarily by suppression of oxidative stress and inflammatory responses, as evidenced by decreased MDA and elevated TAC and GSH levels. Secondarily, GA-Nio was associated with downstream modulation of signaling pathways linked to cellular adaptation, including activation of autophagy (downregulated mTOR and P62 while upregulating beclin-1 and LC3-II) and suppressed Hedgehog pathway activation in adipose tissue. Overall, GA-Nio mitigates obesity-related hepatic injury mainly through antioxidant and anti-inflammatory mechanisms, with secondary involvement of autophagy and Hedgehog pathway regulation, supporting its potential as a therapeutic strategy for obesity-associated liver complications.