Recently, a Chinese scientific research team has achieved a significant breakthrough in steroid research. The relevant findings were published in an international authoritative academic journal, attracting widespread attention from the global scientific community.
This research was jointly completed by the teams of Li Ping, Yang Hua, and Zheng Zuguo from the National Key Laboratory of Multi – Target Natural Medicines at China Pharmaceutical University, and the team of Dai Jianye from Lanzhou University. The research focused on a natural product, ergosterol (ES), a steroid compound structurally similar to cholesterol or phytosterols. Previous studies have shown that sterols have significant lipid – lowering and anti – inflammatory effects and potential therapeutic effects on metabolic diseases. However, the specific functions and mechanisms of action of ergosterol were previously unclear.
Through a series of in – depth experiments, the researchers for the first time revealed that ergosterol can target and activate long – chain acyl – CoA synthetase 1 (ACSL1) in mitochondria, thereby promoting fatty acid β - oxidation and achieving the effects of reducing fatty liver and insulin resistance. This discovery provides new research targets and treatment strategies for the clinical treatment of related diseases.
During the research process, the researchers first conducted in vitro experiments and found that ergosterol could significantly reduce the levels of triglyceride (TG) and total cholesterol (TC) in normal human liver cells and liver cancer cells, confirming its potential lipid – lowering efficacy. Subsequently, in the high – fat diet (HFD) – induced obese mouse model experiment, ergosterol significantly improved the fatty liver degeneration and insulin resistance of the model mice, and its lipid – lowering effect was proven to be related to the fatty acid β - oxidation of liver cell mitochondria.
To explore the mechanism of action of ergosterol, the research team used RNA – seq to identify the significantly modulated genes after ergosterol treatment of cells, and through cMAP database analysis, screened out the top 20 drugs most closely related to these differentially expressed genes. They then speculated that ergosterol might exert its lipid – lowering effect by targeting members of the long – chain acyl – CoA synthetase (ACSL) family. After a series of complex and rigorous experiments, including designing and synthesizing an ergosterol probe (ES – P) that retains its original activity for ABPP technology – based target screening, as well as CETSA/DARTS + WB and SPR experiments, it was finally confirmed that long – chain acyl – CoA synthetase 1 (ACSL1) is the direct target protein of ergosterol.
Further research showed that ergosterol is selectively distributed in mitochondria in liver cells and activates mitochondrial ACSL1 in a concentration – dependent manner to promote fatty acid oxidation. In the functional verification of cell and animal models, the lipid – lowering effect of ergosterol disappeared after the absence of ACSL1, which fully demonstrates that ergosterol exerts its lipid – lowering effect by targeting and activating mitochondrial ACSL1 to accelerate fatty acid β - oxidation.
In addition, the researchers also analyzed the structure – activity relationship of sterols. Through competitive ABPP – reductive demethylation experiments, molecular docking, and mass spectrometry identification, it was found that ergosterol, as a selective allosteric agonist of ACSL1, binds to its C – terminal domain, changing the conformation of ACSL1 from a closed state to an open state and maintaining its activity. Rescue experiments further confirmed that ergosterol regulates lipid metabolism through the allosteric activation of ACSL1. At the same time, the research team found through in – vitro and in – vivo experiments that the combined application of ergosterol and 25 – hydroxycholesterol (25 – HC), an inhibitor of the sterol – sensing domain protein (SCAP), can exert a synergistic lipid – lowering effect, providing a new treatment plan for related diseases.
Experts said that this research result not only deepens the understanding of the mechanism of action of steroid compounds in theory but also brings new hope for the clinical treatment of metabolic diseases. In the future, it is expected to develop more effective treatment drugs and plans based on this discovery, benefiting a large number of patients. This research was strongly supported by projects such as the National Natural Science Foundation of China, reflecting the important role of national scientific research investment in promoting cutting – edge scientific research. Subsequently, the scientific research team will continue to explore in depth, promote the transformation and application of research results, and help improve China’s level in the field of related disease treatment.
Post time: Feb-20-2025