Objective  To develop a machine learning (ML)-based prediction model for assessing the therapeutic effects of resveratrol (RES) on the pathological damage of acute pancreatitis (AP), and to optimize RES administration strategies for AP through validation using an animal model.

Methods AAn ML-based prediction model was constructed using published data. Interpretability analysis was applied to identify high-efficacy zones within the parameter space of administration dose and frequency, which was followed by rigorous screening to select the optimal dosing strategy that balanced therapeutic efficacy and experimental feasibility. A total of 32 C57BL/6 mice were randomly assigned to 4 groups (n = 8 per group), including a control group (Ctrl), an AP model group induced by caerulein (CER) and referred to as CER-AP, a treatment group receiving RES via intraperitoneal injection (RES i.p.), and a treatment group receiving RES via intragastric gavage (RES i.g.). The Ctrl group received intraperitoneal injection of normal saline. The CER-AP and the treatment groups were induced with 10 intraperitoneal injections of CER at 50 μg/kg. RES was administered to the RES i.p. and RES i.g. groups according to the optimal dose and timing predicted by the ML model. Blood and tissue samples were collected 12 hours after the experiment started.

Results The gradient boosting decision tree model, optimized via Hyperopt, yielded the best performance, predicting that the optimal dose and administration frequency were 19.992 mg/kg and 3.828 times, respectively. Accordingly, a regimen of 20 mg/kg RES, administered four times, was used in the animal experiments. Compared with the Ctrl group, the CER-AP group exhibited higher pancreatic pathology scores and elevated levels of serum amylase, lipase, pancreatic myeloperoxidase, and trypsin, with all differences reaching statistical significance (all P < 0.05). The administration of 20 mg/kg RES via both intraperitoneal injection and intragastric gavage mitigated pancreatic inflammatory cell infiltration and necrosis, improved the overall pathology score, and reduced serum amylase, lipase, and pancreatic myeloperoxidase levels to varying degrees (all P < 0.05).

Conclusion A regimen of 20 mg/kg RES administered four times effectively alleviates the severity of CER-induced AP. The therapeutic benefits appear to arise from a multi-target regulatory network that simultaneously suppresses inflammatory cascades, mitigates oxidative stress, and reduces apoptosis, thereby reducing pancreatic tissue damage and systemic inflammatory responses.