Lactylation-driven PDLIM1/PDAP1 axis remodels the inflammatory landscape of acute lung injury: Mechanistic insights and precision intervention

Abstract Acute lung injury (ALI) remains a lethal clinical challenge characterized by an uncontrolled "cytokine storm" arising from dysregulated inflammatory networks. Integrating multi-omics and functional analyses, we identify metabolic reprogramming-driven lactylation as a central orchestrator of inflammatory progression. We demonstrate that PDAP1 lactylation serves as a pivotal metabolic switch for NLRP3 inflammasome activation and selective IL-1β release. Conversely, the functional deficiency of PDLIM1 releases the molecular brake on NF-κB signaling, precipitating a broad-spectrum inflammatory cascade. Leveraging these mechanistic insights, we propose a "dual-target, dual-drug" precision intervention strategy: Progesterone (PT) targets the PDLIM1 axis to quell systemic inflammation, while Ethyl methanesulfonate (EMS) selectively disrupts PDAP1-mediated IL-1β maturation. Furthermore, our findings reveal that these modifications bridge metabolic stress with oxidative damage, involving the NRF2/GPX4-mediated ferroptotic pathway. Validated in both murine models and human iPSC-derived alveolar organoids, this study elucidates a novel metabolic-immune coupling mechanism in pulmonary polarization. By shifting the focus from pan-inflammatory suppression toward precision immunomodulation, our work provides a transformative theoretical paradigm for the management of ALI.