With changes in lifestyle and dietary patterns, the incidence of metabolic diseases such as metabolic dysfunction–associated steatotic liver disease (MASLD) and type 2 diabetes mellitus (T2DM) has been steadily increasing. These conditions have also been showing a trend toward earlier onset, posing a serious threat to human health. However, effective therapeutic interventions are still lacking. Immune cells, particularly bone marrow–derived macrophages, play a critical role in the pathogenesis of metabolic diseases through immune imbalance.

Figure 1. Mechanism by which nitrate regulates the pro-/anti-inflammatory balance of macrophages via Sialin–Rel interaction to prevent and treat metabolic diseases

A research team led by Songlin Wang, Chair Professor and Dean of the School of Medicine at the Southern University of Science and Technology and Director of the SUSTech Homeostatic Medicine Institute (SHMI), in collaboration with Professor Dong Zhang and Associate Professor Guangyong Sun from Beijing Chaoyang Hospital, Capital Medical University, has proposed a new mechanism for immune regulation.

The study suggests that nitrate regulates immune homeostasis through a non-classical nitric oxide (NO) pathway, known as the Sialin–Rel interaction. This pathway modulates the Ctsl–Nrf2 axis, leading to upregulation of anti-inflammatory macrophages and downregulation of pro-inflammatory macrophages in both proportion and function. This immune rebalancing mechanism effectively reshapes systemic immune homeostasis and exerts both preventive and therapeutic effects on metabolic diseases, including MASLD and T2DM.

Their paper, titled “Sodium nitrate protects against metabolic syndrome by Sialin-mediated macrophage rebalance,” has been published in Signal Transduction and Targeted Therapy.

The researchers found that oral nitrate can effectively prevent and treat metabolic syndrome at an early stage by modulating macrophage homeostasis. While the classical nitrate–nitrite–NO pathway is known to require gut microbiota, they observed that oral nitrate still exerts protective effects in a MASLD model established in relatively germ-free mice. This suggests the existence of a non-NO–dependent pathway.

Analysis of clinical samples revealed a significant reduction of Sialin expression in hepatic macrophages of MASLD patients. In MASLD animal models, nitrate markedly upregulated Sialin expression in macrophages. However, in a MASLD model induced in Sialin double-knockout mice, this nitrate-mediated upregulation of macrophage Sialin was substantially attenuated.

Using an in vitro primary bone marrow–derived macrophage differentiation model, the team found that Sialin interacts with Rel. Molecular docking experiments predicted and validated that Sialin regulates macrophage homeostasis via the downstream Ctsl–Nrf2 pathway. This manifests as a decrease in pro-inflammatory macrophages and an increase in anti-inflammatory macrophages, both in proportion and function, thereby reshaping the macrophage immune balance and playing a key role in preventing and treating metabolic diseases.

This study not only identified that nitrate regulates macrophage homeostasis via a non-NO pathway (the Sialin–Ctsl–Nrf2 axis), but also provides a novel strategy for the prevention and treatment of metabolic diseases, including MASLD and T2DM.

Dr. Shaorong Li from Beijing Stomatological Hospital, Capital Medical University is the first author of the paper. Professor Dong Zhang, Associate Professor Guangyong Sun, and Chair Professor Songlin Wang are co-corresponding authors. Other contributors to this work include Chair Professor Guozhi Xiao, Principal Investigators Mo Chen and Renhong Yan, and Ph.D. candidate Songyue Wu, all from the School of Medicine and SHMI at SUSTech.

Paper link: https://doi.org/10.1038/s41392-025-02418-1

To read all stories about SUSTech science, subscribe to the monthly SUSTech Newsletter.