A research team led by Dr. Dong Zhang and Dr. Guangyong Sun from Beijing Chaoyang Hospital, Capital Medical University, in collaboration with Dr. Zhongtao Zhang from Beijing Friendship Hospital, Capital Medical University, has recently published a study in Metabolism-Clinical and Experimental. The study, titled “CD36-mediated uptake of oxidized LDL induces double-negative regulatory T cell ferroptosis in metabolic dysfunction-associated steatotic liver disease”, explores how oxidized low-density lipoprotein (oxLDL) regulates ferroptosis in double-negative T (DNT) cells via CD36, thereby influencing the progression of metabolic dysfunction-associated steatotic liver disease (MASLD). Doctoral candidate Yunxiong Wei and master's student Yuan Jiang are co-first authors of the study, while Dr. Dong Zhang, Dr. Guangyong Sun, and Dr. Zhongtao Zhang serve as co-corresponding authors.MASLD: A Growing Health Concern
MASLD is a common chronic liver disease with an increasing prevalence worldwide. In China’s urban population, the prevalence of MASLD is as high as 28.4%, and among individuals with obesity, the rate exceeds 60%. The disease typically progresses from hepatic steatosis to more severe conditions such as metabolic dysfunction-associated steatohepatitis (MASH), liver fibrosis, cirrhosis, and even hepatocellular carcinoma. Despite its growing burden, there is still no effective treatment for MASLD or MASH. The progression of MASLD is closely linked to hepatic inflammation and immune imbalance, making these areas critical targets for potential therapeutic interventions.
Unraveling the Role of Double-Negative T Cells in MASLD
Professor Zhang Dong’s research team has long been dedicated to the study of CD4⁻CD8⁻ double-negative T (DNT) cells. Their previous work has made pioneering contributions in identifying DNT cell subtypes, origins, antigen recognition mechanisms, and immunoregulatory functions, with landmark findings published in Blood (2007), Diabetologia (2011), Nature Communications (2019), Journal of Autoimmunity (2021), and Science Bulletin (2025). The team was the first to demonstrate the crucial role of DNT cells in maintaining hepatic immune homeostasis.
In MASLD, the survival and immunosuppressive function of DNT cells are significantly compromised, leading to immune imbalance and increased hepatic inflammation. Previous studies published in Nature Communications (2021) and Cellular and Molecular Gastroenterology and Hepatology (2022) established that dysfunctional DNT cells contribute to MASLD progression, but the precise mechanisms underlying this dysfunction remained unclear.
New Discovery: How oxLDL Drives Ferroptosis in DNT Cells
The study found that serum oxLDL levels were significantly elevated in both MASLD patients and MASLD mouse models. Notably, these increased oxLDL levels were closely associated with a decline in DNT cell numbers and function. Further experiments demonstrated that oxLDL activates the NF-κB signaling pathway in DNT cells, leading to an upregulation of CD36 expression. This increase in CD36 facilitates the uptake of oxLDL by DNT cells, triggering a cascade of molecular events.
The uptake of oxLDL upregulates hypoxia-inducible factor-1α (Hif-1α) expression in DNT cells, which subsequently binds to the ACSL4 promoter region and enhances its expression. This cascade induces ferroptosis in DNT cells via CD36-mediated mechanisms, leading to their functional impairment. As a result, the loss of functional DNT cells disrupts hepatic immune homeostasis and accelerates MASLD progression.
Potential for New Therapeutic Strategies
The study further demonstrated that the infusion of CD36-deficient DNT cells provided superior protection against oxLDL-induced ferroptosis compared to wild-type DNT cells. CD36-deficient DNT cells were more effective in maintaining hepatic immune balance and mitigating MASLD severity. These findings suggest that targeting CD36 or modulating DNT cell survival could be a promising therapeutic strategy for MASLD.
Conclusion and Future Directions
This research provides the first detailed mechanistic insight into how oxLDL drives ferroptosis in DNT cells, contributing to MASLD progression. By identifying the CD36-Hif-1α-ACSL4 axis as a key regulator of DNT cell dysfunction, the study opens new avenues for immunotherapy in MASLD. Future research will focus on optimizing DNT cell-targeted interventions and exploring clinical applications for MASLD treatment.
