A short-term high-fat diet induced acute postoperative pain priming through impairing SerpinB6 protein-mediated M2...

Postoperative pain remains a major perioperative challenge, with undermanagement leading to delayed recovery, poor patient satisfaction, morbidity and the potential development of chronic pain. Perioperative dietary intake, such as a high-fat diet (HFD), has emerged as an essential regulator of postoperative pain sensitivity. While long-term HFD induces direct neuronal sensitization to prolong pain responses, the impact of short-term HFD on perioperative pain and its underlying mechanisms is yet to be characterized. Here, we investigated the role of short-term HFD intervention in postoperative pain using the hindpaw incision (HPI) model in male mice. Pain behavioral tests showed that two weeks of HFD exposure significantly prolonged mechanical and thermal nociceptive responses in HPI compared to the normal diet. Mechanistically, short-term HFD disrupted lipid metabolic homeostasis, which dysregulated the local immune microenvironment. It shifted macrophage polarization from anti-inflammatory M2 to pro-inflammatory M1 phenotype and upregulated pro-nociceptive cytokines (e.g., TNF-α, IL-6) in the incised paw tissues. Notably, SerpinB6, a key mediator linking lipid metabolism to immune regulation, was downregulated by short-term HFD. Local restoration of SerpinB6 normalized macrophage polarization, reduced pro-inflammatory cytokines (IL-6, TNF-α), and alleviated pain hypersensitivity. Furthermore, SerpinB6 exerted its effect by restoring Sirt1 expression and attenuating ERK phosphorylation. Collectively, our findings revealed that short-term HFD primed acute postoperative pain via SerpinB6 protein downregulation and subsequent immune microenvironment dysregulation. This study highlighted that short-term dietary intervention and SerpinB6 are potential therapeutic strategies for perioperative pain management.