Post-translational modification crosstalk in acute pancreatitis: linking acinar stress to innate immune amplification and tissue repair

Acute pancreatitis (AP) is a sterile inflammatory disease initiated by acinar cell stress and amplified through innate immune, vascular, and inter-organ responses, yet effective disease-modifying therapies remain unavailable. Although premature digestive enzyme activation, organelle stress, sterile inflammation, and microvascular failure are well-recognized features of AP, the mechanisms linking early acinar stress to coordinated injury across epithelial, immune, stromal, and vascular compartments remain insufficiently integrated. Emerging evidence suggests that post-translational modifications (PTMs) constitute a dynamic regulatory layer through which metabolic stress is converted into damage-associated molecular pattern release, innate immune activation, inflammatory cell death, tissue repair, and disease progression. This review examines how metabolic stress remodels lactylation, acetylation, phosphorylation, ubiquitination, and related PTMs in AP and how their functional convergence and selected PTM interactions shape DAMP sensing, inflammasome activation, macrophage reprogramming, neutrophil recruitment and extracellular trap formation, cytokine amplification, mitochondrial dysfunction, apoptosis, pyroptosis, ferroptosis, microvascular barrier failure, and systemic complications. We propose an integrated framework linking acinar stress to PTM remodeling, innate immune amplification, and inflammatory resolution. Across acinar, ductal, immune, stellate, and endothelial compartments, PTMs regulate protein stability, subcellular localization, transcriptional programs, organelle quality control, and intercellular signaling. Selected PTM pathways exhibit stage- and cell-dependent effects; for example, lactate-associated lactylation may exacerbate early ferroptotic injury while promoting reparative macrophage polarization during recovery. This framework positions PTM remodeling as a context-dependent immunometabolic control system while recognizing that direct molecular PTM-PTM crosstalk remains incompletely demonstrated in AP.