Objective: To screen potential pathogenic metabolites of acute pancreatitis (AP) and explore the molecular mechanism of α-ketoglutarate (αKG) regulating DNA damage repair protein, X ray repair cross-complementing protein 3 (XRCC3) to induce AP based on animal and cell models. Methods: The study first conducted a Mendelian randomization (MR) study combined with two rounds of independent meta-analysis to screen metabolites related to the onset of acute pancreatitis from a genetic perspective, and used the inverse variance weighted (IVW) method to evaluate the causal effect of metabolites on AP. Subsequently, AP animal models in C57BL/6 mice and AR42J cell models were constructed. The effects of αKG on pancreatic acinar cell injury and inflammatory response were verified by intraperitoneal injection of αKG and co-culture with the medium, respectively. The detection indicators included cell viability, levels of inflammatory factors, and histopathological changes. In addition, RNA sequencing was used to analyze the whole transcriptome differences in AR42J cells before and after αKG treatment, and the expression changes of XRCC3 and its role in the onset of AP were verified by immunohistochemistry and Western Blot techniques. Results: The MR study and meta-analysis results showed that αKG had a positive causal relationship with the onset of acute pancreatitis, while indolepropionate (INDO) showed a potential protective effect. Cell experiments indicated that 10 μmol/L of αKG could significantly inhibit the viability of AR42J cells and promote the secretion of inflammatory factors such as interleukin-6 (IL-6) and interleukin-1β (IL-1β). In the animal model, intraperitoneal injection of αKG could induce the occurrence of AP in mice, manifested as pancreatic tissue edema, acinar cell injury, and elevated serum inflammatory factor levels. Through in-depth mechanism research using RNA-seq, it was found that αKG exacerbated acinar cell injury by inhibiting the expression of XRCC3 and weakening the DNA damage repair ability. The expression of XRCC3 in AR42J cells was significantly down regulated after αKG treatment, which was verified by immunohistochemistry and Western Blot. Additionally, over expression of XRCC3 could partially reverse the damage effect of αKG on acinar cells. Conclusion: This study is the first to confirm at the genetic level that αKG is a pathogenic metabolite of AP, which exacerbates acinar cell injury and inflammatory response by inhibiting the XRCC3-mediated DNA repair pathway. This discovery provides a new perspective for the metabolic mechanism research of AP and suggests that targeting the αKG-XRCC3 axis may be a potential therapeutic strategy.