Non‐lethal sonodynamic therapy inhibits high glucose and palmitate‐induced macrophage inflammasome activation through mtROS‐DRP1‐mitophagy pathway

Obesity plays a crucial role in the development and progression of type 2 diabetes mellitus (T2DM) by causing excessive release of free fatty acid from adipose tissue, which in turn leads to systemic infiltration of macrophages. In individuals with T2DM, the infiltration of macrophages into pancreatic islets results in islet inflammation that impairs beta cell function, as evidenced by increased apoptosis and decreased glucose-stimulated insulin secretion. The present study aimed to investigate the effects of non-lethal sonodynamic therapy (NL-SDT) on bone marrow-derived macrophages (BMDMs) exposed to high glucose and palmitic acid (HG/PA). These findings indicate that NL-SDT facilitates the expression of DRP1 through the transient production of mitochondrial ROS, which subsequently promotes mitophagy. This mitophagy was shown to limit the activation of the NLRP3 inflammasome and the secretion of IL-1β in BMDMs exposed to HG/PA. In co-culture experiments, beta cells exhibited significant dysfunction when interacting with HG/PA-treated BMDMs. However, this dysfunction was markedly alleviated when the BMDMs had undergone NL-SDT treatment. Moreover, NL-SDT was found to lower blood glucose levels and elevate serum insulin concentrations in db/db mice. Furthermore, NL-SDT effectively reduced the infiltration of F4/80-positive macrophages and the expression of CASP1 within islets. These findings provide fundamental insights into the mechanisms through which NL-SDT may serve as a promising approach for the treatment of T2DM.