PANoptosis is a comprehensive form of cell death regulation that involves the interplay of pyroptosis, apoptosis, and necrosis. As a key regulator of PANoptosis, TAK1 plays a crucial role in multiple cell death pathways. However, its specific mechanism in the process of diabetic wound (DW) healing remains unclear. This study aimed to explore the role of TAK1 in regulating PANoptosis and its impact on DW healing.

We used immunofluorescence, TUNEL staining, and EthD-Ⅲ staining to analyse the relationship between TAK1 activity and PANoptosis. RNA sequencing was used to investigate the regulatory role of TAK1 and the NF-κB pathway under high-glucose conditions. Additionally, molecular docking and coimmunoprecipitation experiments were performed to verify the interaction between TAK1 and p65. Finally, a mouse model was used to study the effects of TAK1 knockdown on wound healing.

Our findings revealed that PANoptosis is significantly present in DW, with markedly upregulated TAK1 expression under high-glucose conditions. The inhibition of TAK1 expression significantly reduced cell death and promoted cell proliferation and migration. Mechanistically, TAK1 interacts with p65 through the NF-κB pathway, activating downstream signals that exacerbate cell damage in a high-glucose environment. TAK1 knockdown significantly suppressed PANoptosis, promoted microvascular and collagen formation, reduced inflammation, and further accelerated wound healing.

TAK1 regulates PANoptosis by activating the NF-κB signalling pathway, thereby playing a crucial role in DW healing. Inhibiting TAK1 may represent a potential strategy to improve wound healing, with significant potential for clinical application.