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

Abstract 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 2+ signalling, and reducing tissue damage and inflammation, without overt toxicity to healthy acinar cells in the absence of injurious stimuli. In contrast, in CP, a disease marked by fibrosis and prevailing apoptotic loss of parenchyma, BCL2 inhibition provides no benefit and may exacerbate acinar atrophy and fibrogenesis. We discuss the mechanistic basis of these divergent effects, including the role of BCL2 proteins in cell death regulation and calcium dynamics. Finally, we highlight future directions, including the rationale for clinical testing of Venetoclax in AP, and discuss cautionary considerations for its use in CP, particularly in patients with coexisting conditions such as leukaemia, who may already be receiving BH3 mimetics.