Oxidized Low- and High-Density Lipoproteins (oxLDL and oxHDL) in the Pathogenesis of MASLD/MASH

Metabolic dysfunction-associated steatotic liver disease (MASLD) affects 32% of the world’s population. Its pathogenesis is closely linked to metabolic dysfunction and lipotoxicity. The main pathogenic processes in MASLD are lipotoxicity, oxidative stress, and activation of inflammasome assembly. These processes sustain chronic inflammation, recruit immune cells to the liver, activate Kupffer cells, and subsequently drive the differentiation of hepatic stellate cells into myofibroblasts and the development of fibrosis. Oxidized low- and high-density lipoproteins (oxLDL and oxHDL) are involved in the progression of MASLD to metabolic dysfunction-associated steatohepatitis (MASH). OxLDL and oxHDL are formed through enzymatic oxidation (involving NOX, MPO, and 15-LOX) as well as non-enzymatic oxidation of native lipoproteins and acquire an affinity for scavenger receptors. Scavenger receptors are often associated with Toll-like receptors (TLRs) 2/4 and are involved in the pathogenesis of the transition from MASLD to MASH and fibrosis, in which activation of the LOX-1/NF κB/NLRP3 axis plays a central role. This review examines drugs in clinical trials that act on downstream signaling pathways. Studies of inhibitors targeting components of this signaling cascade have shown promising results. Analysis of therapeutic strategies for MASH suggests that a combination of lowering lipoprotein levels and blocking inflammatory signaling may be most effective, as it targets both the metabolic and inflammatory components of the disease.