Chlorogenic acid targets SLC37A2 to inhibit macrophage activation via ER-dependent NF-κB and NLRP3 signaling pathways against sepsis-induced acute lung injury.

Sepsis-induced acute lung injury (SI-ALI) requires urgent treatment due to severe inflammation. Our study found chlorogenic acid (CGA) suppressed LPS-induced macrophage activation by lowering NO, TNF-α, and IL-6. TPP-based strategies identified SLC37A2 as the direct target of CGA, validated by CETSA/MST. Molecular docking indicated CGA-SLC37A2 hydrogen bonding. CGA alleviated endoplasmic reticulum stress via SLC37A2, inhibiting TLR4/NF-κB and NLRP3 pathways to reduce inflammation. In SI-ALI mice and zebrafish models, CGA mitigated lung injury through these mechanisms taken together. This work highlights the therapeutic potential of CGA for SI-ALI and the critical role of SLC37A2 in combating infectious pneumonia.