LAPTM5 Downregulation‐Driven VAMP8 Phosphorylation Impairs Autophagosome‐Lysosome Fusion and Aggravates Septic Acute Lung Injury

ABSTRACT Sepsis‐induced acute lung injury (ALI) is a lethal inflammatory condition with limited therapeutic options. Macrophage autophagic homeostasis is essential to constrain septic ALI inflammation, though its upstream regulation remains elusive. Here, we report that lysosomal‐associated protein transmembrane 5 (LAPTM5) is markedly downregulated in peripheral blood mononuclear cells (PBMCs) from septic ALI patients and alveolar macrophages (AMs) of septic mice, with its expression correlating inversely with the SOFA score. Macrophage‐specific depletion of Laptm5 exacerbated mouse ALI symptoms, whereas AAV‐mediated Laptm5 overexpression yielded diametrically opposite effects. Mechanistically, LPS stimulation promotes FOXB1 nuclear accumulation, which in turn represses the transcription and protein expression of LAPTM5. Furthermore, LAPTM5 acts as a molecular scaffold bridging PGAM5 and VAMP8, mediating PGAM5‐dependent VAMP8 dephosphorylation to promote autophagosome‐lysosome fusion and autophagic flux. This cascade clears damaged mitochondria, thereby mitigating intracellular oxidative stress and inflammation. This study defines macrophage LAPTM5 as a critical autophagy regulator that mitigates septic ALI, providing a potential avenue for future therapeutic exploration.