Linoleic acid (LA), an essential fatty acid, has emerged as a pivotal regulator in disorders associated with inflammation in recent years; however, the underlying mechanisms are still not completely understood. We utilized network pharmacology and experimental methodologies to elucidate the mechanisms underlying the anti-inflammatory effects of LA. Our network pharmacology analysis revealed that LA shares common targets with sepsis. These targets are enriched in various pathways comprising C-type signaling pathway, PI3K-Akt signaling pathway, toll-like receptor signaling pathway, neutrophil extracellular trap formation, AMPK signaling pathway, and autophagy-animal. These findings suggest that LA may exert regulatory effects on inflammation and autophagy during sepsis. Subsequently, we established in vivo and ex vivo models of sepsis using lipopolysaccharide (LPS) in experimental study. Treatment with LA reduced lung damage in mice with LPS-induced lung injury, and reduced tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in plasma, bronchoalveolar lavage fluid (BALF), and peritoneal lavage fluid (PLF). LA also decreased the production of TNF-α and IL-6 in RAW264.7 macrophages exposed to LPS. In LPS-induced RAW264.7 macrophages, LA induced an elevation in LC3-II while causing a reduction in p62, which was associated with downregulation of toll-like receptor 4 (TLR4). We utilized 3-methyladenine (3-MA) to inhibit the autophagic activity, which reversed the modulatory effects of LA on LC3-II and p62. 3-MA also prevented the decline in TLR4 expression along with reduction in pro-inflammatory cytokines secretion. Our findings suggest that the activation of autophagy by LA may lead to the downregulation of TLR4, thereby exerting its anti-inflammatory effects.

Chongqing Medical University Department of Pathophysiology Chongqing 400016 China

University Town Hospital of Chongqing Medical University Department of Emergency and Critical Care Medicine Chongqing 401331 China

University Town Hospital of Chongqing Medical University Department of Respiratory and Critical Care Medicine Chongqing 401331 China

University Town Hospital of Chongqing Medical University Medical Sciences Research Center Chongqing 401331 China

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