Hexiao Tang, Congkuan Song, Guiomar Correia, Changsheng Li, Daoquan Liu, Xuefeng Zhou
Introduction: Acute lung injury (ALI) remains a lethal clinical challenge driven by an uncontrolled "cytokine storm" resulting from dysregulated inflammatory networks. The metabolic and molecular mechanisms orchestrating this process remain incompletely understood. Methods: We integrated multi-omics profiling with functional analyses in murine models and human iPSC-derived alveolar organoids. Key molecular players were identified through loss-of-function and pharmacological interventions, and the effects of a dual-target strategy using progesterone (PT) and ethyl methanesulfonate (EMS) were evaluated. Results: Metabolic reprogramming-driven lactylation emerged as a central orchestrator of inflammatory progression. PDAP1 lactylation acts as a pivotal metabolic switch for NLRP3 inflammasome activation and selective IL-1β release. Functional deficiency of PDLIM1 releases the molecular brake on NF-κB signaling, precipitating a broad-spectrum inflammatory cascade. These modifications bridge metabolic stress with oxidative damage via the NRF2/GPX4-mediated ferroptotic pathway. The "dual-target, dual-drug" intervention-PT targeting the PDLIM1 axis and EMS selectively disrupting PDAP1-mediated IL-1β maturation-effectively quelled systemic inflammation and attenuated ALI pathology in both in vivo and organoid models. Discussion: This study elucidates a novel metabolic-immune coupling mechanism in pulmonary polarization, shifting the focus from pan-inflammatory suppression toward precision immunomodulation. The findings provide a transformative theoretical paradigm for the management of ALI.