An H₂S-releasing oridonin derivative protects HaCaT cells against metabolic stress via PI3K/AKT/Nrf2 signaling

The chronic hyperglycemia and its-associated metabolic changes often lead to impaired wound healing, which seriously affects the quality of life of diabetic patients. Oxidative stress and apoptosis are key factors that impede epidermal cell proliferation and migration and delay wound healing. The aim of this study was to investigate the protective effect of a novel hydrogen sulfide (H₂S)-releasing oridonin derivative (OAc-Ph-ADT) on epidermal HaCaT cells against a high-glucose and high-fat environment in vitro. Mechanistic studies showed that OAc-Ph-ADT exerted its antioxidant effects by activating the PI3K/AKT/Nrf2 signaling pathway. Specifically, it increased PI3K and phosphorylated-AKT expression, and promotes Nrf2 nuclear translocation, which in turn enhances the mRNA and protein expression of downstream antioxidant factors (HO-1, SOD2 and NQO1). In addition, OAc-Ph-ADT significantly reduced apoptosis by inhibiting the decrease in mitochondrial membrane potential and decreasing the expression of apoptosis-related proteins (Bax, Cleaved-Caspase 3/9). It was also observed that OAc-Ph-ADT up-regulated the expression of cystathionine β-synthase (CBS) via Nrf2, which further promoted the synthesis of endogenous H₂S, resulting in positive feedback regulation. In summary, this paper elucidated through systematic in vitro experiments that OAc-Ph-ADT has a protective effect against epidermal cell damage in a high-glucose and high-fat environment, revealing its potential as a candidate molecule for diabetic wound treatment, and this novel H₂S-releasing oridonin derivative has a potential application as a diabetic wound healing promoter.