Hepatic steatosis, oxidative stress, and inflammatory signaling

Hepatic steatosis, oxidative stress, and inflammatory signaling describes the core pathophysiological triad driving the progression of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) and its inflammatory stage, Metabolic Dysfunction-Associated Steatohepatitis (MASH) (Source: NIH, PubMed). Hepatic steatosis is characterized by the excessive accumulation of triglycerides in hepatocytes, which predisposes the liver to lipotoxic injury (Source: StatPearls). This lipid overload leads to oxidative stress, primarily through mitochondrial dysfunction and the upregulation of pro-oxidant enzymes like CYP2E1, resulting in the overproduction of reactive oxygen species (ROS) (Source: Nature Reviews Gastroenterology & Hepatology). These ROS, along with lipid peroxidation products, activate key inflammatory signaling pathways such as NF-κB and JNK, which trigger the production of pro-inflammatory cytokines like TNF-α and IL-6 (Source: Journal of Hepatology). While this triad is not a single molecular target, it represents a complex network of interactions that are the focus of multi-target therapeutic approaches, including PPAR agonists and thyroid hormone receptor-beta (THR-β) selective agonists like Resmetirom (Source: FDA, NEJM).

Other names

NAFLD pathogenesisMASH progressionLipotoxicity-driven liver injuryMultiple-hit hypothesis

Therapeutic intervention typically involves activating PPAR receptors to improve lipid metabolism, utilizing antioxidants to neutralize reactive oxygen species, or inhibiting cytokine signaling to reduce chronic inflammation.