PANoptosis in diabetes: immunometabolic insights and treatments

The core pathological mechanism of diabetes mellitus and its complications is rooted in the interactive regulation between immunometabolic dysregulation and inflammatory programmed cell death, with PANoptosis serving as a critical hub in this process. PANoptosis is a distinct innate immune-mediated inflammatory lytic cell death pathway initiated by pattern-recognition receptors and propagated via the PANoptosome complex, which plays a critical hub role in the interactive regulation between immunometabolic dysregulation and inflammatory programmed cell death in diabetes. Under diabetic conditions, metabolic stressors, including chronic hyperglycemia and lipotoxicity, directly promote PANoptosome assembly by disrupting cellular energy balance, inducing mitochondrial dysfunction, and accumulating reactive oxygen species. Meanwhile, the activation of immune signaling pathways such as TLR/NLR further amplifies the PANoptotic effect, leading to pancreatic β-cell loss, exacerbated adipose tissue inflammation, and vascular endothelial damage, ultimately driving the progression of complications such as nephropathy, retinopathy, and neuropathy. There exists a bidirectional regulation between PANoptosis and immunometabolism: metabolic intermediates such as succinate and lactate can enhance the expression of PANoptosis-related molecules by activating the SUCNR1-NF-κB pathway or regulating histone lactylation; in turn, DAMPs released by PANoptosis, such as HMGB1 and IAPP, reshape the metabolic phenotype of immune cells by activating TLR/RAGE signaling. This review systematically synthesizes the immunometabolic regulatory mechanisms of PANoptosis in diabetes and its complications, clarifies its cell-specific roles in β-cells, immune cells, and vascular tissues, and evaluates therapeutic strategies targeting the metabolic-immune crosstalk axis and core PANoptotic components, providing new theoretical basis and potential targets for precision intervention in diabetes and its complications.