3,4-Dimethoxychalcone-induced caloric restriction inhibits PANoptosis to promote ischemic and diabetic skin flap survival: experimental studies
Gaoxiang Yu, Jiayi Zhao, Xiao-Xiao Zhu, Ningning Yang, Junsheng Lou, Zhuliu Chen, Haojie Zhang, Tafadzwa Chaire, Weiyang Gao, Yuepiao Cai, Xiangyang Wang, Jian Ding, Jian Xiao, Kailiang Zhou, Jianjun Qi
Abstract
BACKGROUND: Ischemic necrosis frequently affects the distal portion of skin flaps, particularly in diabetic patients. PANoptosis, a form of inflammatory programmed cell death, is implicated in vascular damage. This study examined whether 3,4-dimethoxychalcone (3,4-DC), a novel caloric restriction (CR) mimetic, could inhibit PANoptosis and promote the survival of ischemic and diabetic flaps. METHODS: Flap viability was evaluated using laser Doppler blood flow imaging and histological analysis. Western blotting and immunofluorescence were used to assess PANoptosis and autophagy. Quantitative PCR was used to measure microRNA levels. Caspase-1 knockout and db/db mice were used to explore the effects of 3,4-DC on pyroptosis and diabetic complications. RESULTS: 3,4-DC significantly improved ischemic flap survival and enhanced tissue perfusion. PANoptosis was inhibited, and autophagy was activated following 3,4-DC treatment, whereas these effects were abolished by the autophagy inhibitor chloroquine. Transcription factor EB (TFEB) inhibition reduced autophagy and reversed the protective effects of 3,4-DC. miR-107-3p was identified as a 3,4-DC-responsive microRNA that modulates TFEB nuclear translocation through the miR-107-3p/Wnt3a/mTOR pathway. Similar therapeutic effects were observed in diabetic flaps. CONCLUSION: 3,4-DC promotes the survival of ischemic and diabetic skin flaps by activating autophagy and inhibiting PANoptosis through the miR-107-3p/Wnt3a/mTOR/TFEB axis.