GDF15 attenuates sepsis-induced acute lung injury by suppressing the HIF-1α/LDHA pathway

Sepsis-associated acute lung injury (ALI) is characterized by endothelial inflammation and metabolic reprogramming. Growth Differentiation Factor 15 (GDF15), a stress-inducible cytokine, may regulate immunometabolic crosstalk, but its endothelial-specific role remains undefined.

Using LPS-induced septic mice and human endothelial cells, GDF15 expression was dysregulated via AAV-mediated overexpression or siRNA knockdown. Pharmacological modulators included: HIF-1α inhibitor BAY 87-2243, HIF-1α activator 1,4-DPCA, LDHA inhibitor FX-11, and sodium lactate. Endothelial inflammation was evaluated through adhesion molecules (ICAM-1, VCAM-1, VEGF-A) and cytokines (TNF-α, IL-6) at protein levels.

GDF15 was upregulated in pulmonary endothelia of septic mice and contributed to endothelial dysfunction, evidenced by elevated adhesion molecules (ICAM-1/VCAM-1/VEGF-A), cytokines (TNF-α/IL-6), and impaired barrier repair. GDF15 overexpression alleviated lung injury and inflammation, while its knockdown aggravated pathology. Mechanistic studies revealed that GDF15 inhibits the HIF-1α/LDHA glycolytic axis activated by LPS, reducing cytokine storm and leukocyte adhesion. Critically, HIF-1α inhibitor (BAY 87-2243) and LDHA inhibitor (FX-11) phenocopied GDF15 protection, whereas HIF-1α activator (1,4-DPCA) and sodium lactate negated it, establishing HIF-1α/LDHA as the primary effector pathway.

GDF15 emerges as a critical endothelial protector in sepsis by suppressing HIF-1α/LDHA-mediated immunometabolic dysregulation. Its synergistic interplay with glycolytic inhibitors highlights a novel therapeutic strategy to target both inflammatory and metabolic drivers of ALI.