Am J Physiol Endocrinol Metab. 2024 Feb 21. doi: 10.1152/ajpendo.00406.2023. Online ahead of print.

ABSTRACT

Larsucosterol (25-Hydroxycholesterol 3-sulfate, 25HC3S), a potent endogenous epigenetic regulator, has been reported to play a significant role in lipid metabolism, inflammatory responses, and cell survival. Administration of 25HC3S has been shown to decrease lipid accumulation in hepatocytes, suppress LPS- and TNFα-induced inflammatory responses in macrophages, alleviate LPS- and ATMP-induced multiple organ injury, and decreases mortalities in animal models. Results from phase 1 and 2 clinical trials have shown that 25HC3S has potential as a biomedicine for the treatment of acute and chronic liver diseases. Recent evidence suggests that 25HC3S is a promising candidate for treating alcohol-associated hepatitis with positive results from a phase 2a clinical trial, and for MASH from a phase 1b clinical trial. In this review, we present a culmination of our recent research efforts spanning two decades. We summarize the discovery, physiological and pharmacological mechanisms, and clinical applications of 25HC3S. Furthermore, we elucidate the pathophysiological pathways of Metabolic Dysfunction-associated Steatotic Liver Diseases (MASLD), Metabolic Associated Steatohepatitis (MASH), and acute liver injuries. A central focus of the review is the exploration of the therapeutic potential of 25HC3S in treating life-threatening conditions, including acetaminophen overdose, endotoxin shock, MASLD, MASH, hepatectomy, and alcoholic hepatitis.

PMID:38381400 | DOI:10.1152/ajpendo.00406.2023