BCL2 inhibition in acute and chronic pancreatitis - is there a therapeutic perspective?

Necrotic death of pancreatic acinar cells leads to premature activation of digestive enzymes and is a central driver of inflammation in acute pancreatitis (AP). In contrast, apoptosis is a non-lytic, regulated form of cell death that prevents the release of intracellular content and is therefore considered less damaging. The induction of the intrinsic apoptotic pathway is tightly regulated by the balance between pro- and anti-apoptotic members of the BCL2 protein family. Pharmacological inhibitors of anti-apoptotic BCL2 proteins - BH3 mimetics - have thus emerged as tools to therapeutically shift cell fate from necrosis to apoptosis. Early-generation BH3 mimetics such as HA14-1 and BH3I-2' used to validate this concept were hindered by limited potency and significant off-target effects, including disruption of calcium homeostasis. More selective and potent second-generation agents - particularly Navitoclax (ABT-263) and Venetoclax (ABT-199) - have overcome these limitations, with Venetoclax now approved for clinical use in haematological malignancies. Here, we explore the therapeutic potential of BCL2 inhibitors in pancreatic diseases, with a focus on AP and a comparison to chronic pancreatitis (CP). In AP models, BCL2 inhibition - especially with Venetoclax - redirects cell death from necrosis to apoptosis, preserving intracellular ATP, attenuating aberrant Ca