Schisandrin B exacerbates acute pancreatitis by driving pathological pancreatic secretion

Schisandrin B (SchB), a natural lignan with reported organ-protective effects, was hypothesized to ameliorate severe acute pancreatitis (SAP). We investigated the effects of SchB (30 and 60 mg/kg) in a caerulein-induced mouse model of SAP using histological, biochemical, and transcriptomic analyses. Contrary to our hypothesis, SchB administration significantly exacerbated pancreatitis, evidenced by more severe pancreatic edema, necrosis, inflammatory infiltration, and significantly higher serum α-amylase levels compared to vehicle-treated controls. Global RNA sequencing (RNA-seq) of pancreatic tissue identified "Pancreatic Secretion" as a key upregulated pathway. SchB induced a massive transcriptional upregulation of genes encoding digestive enzymes, including trypsinogens, lipases, and amylase. Concurrently, the gene for the calcium efflux pump Atp2a3 was downregulated, suggesting a mechanism for intracellular calcium overload. In conclusion, SchB exacerbates acute pancreatitis, likely by transcriptionally promoting the overproduction of digestive enzymes, leading to enhanced auto-digestion. These findings reveal a novel, context-specific harmful effect of SchB, challenging its perception as a universally protective agent and urging caution in its use for patients with or at risk for pancreatic diseases.