Understanding Metabolic Reprogramming in Reparative Macrophages

Chronic or non-healing wounds affecting over 2.5% of the U.S. population, present significant medical challenges, escalating the risk of infection, tissue degradation, and potential amputation. Macrophages, crucial for combating infections and controlling inflammation, play a key role in maintaining tissue homeostasis and promoting wound healing. Recent studies highlight the crucial role of metabolic reprogramming in macrophages responding to inflammation. Metabolic shifts impact the availability of essential metabolites that serve as cofactors or substrates for epigenetic enzymes, thereby influencing genome accessibility and regulating macrophage differentiation and function. Despite this, the specific nexus between metabolic rewiring and epigenetic modification governing the reparative function of macrophages within both inflamed and injured tissues remains largely unexplored. We recently discovered that a key component of the serine synthesis pathway, phosphoserine aminotransferase 1 (PSAT1), is an essential metabolic checkpoint in macrophages for anti-inflammatory (M2) activity to control tissue inflammation. Our preliminary data reveal that PSAT1's metabolic role in serine generation within M2 macrophages is integral for mitochondrial heme synthesis, respiratory activity, and the regulation of intracellular levels of α-ketoglutarate (α-KG), a crucial metabolite in the mitochondrial TCA cycle and a substrate for histone demethylation. As a result, the tri-methylation of lysine 27 on histone H3 (H3K27me3), a repressive histone mark associated with transcriptional silencing, is increased in the absence of PSAT1, significantly impairing macrophage anti-inflammatory function. These exciting data support a novel and provocative hypothesis that the metabolic reprogramming of serine synthesis, regulated by PSAT1, can influence the mitochondrial homeostasis and epigenetic accessibility of reparative M2 macrophages in the context of tissue injury and inflammation. In this proposed project, I will advance our interesting findings and scrutinize the hypothesis rigorously with the following two directions: 1) Elucidate the role of PSAT1 in macrophage mitochondrial homeostasis and reparative activity. 2) Investigate the interplay between PSAT1 metabolism and epigenetic modification in reparative macrophages. I will employ incisive transcriptomics, metabolomics, and immunological approaches to achieve these goals. The results will answer a fundamental and long-standing question surrounding the role of metabolic rewiring in macrophages for wound healing and tissue resolution. Moreover, this project will break new ground, providing crucial insights on the much-needed crosstalk between metabolism and epigenetics. Project Number: 1R35GM161784-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of General Medical Sciences (NIGMS) | Principal Investigator: Stanley Huang | Institution: OHIO STATE UNIVERSITY, Columbus, OH | Award Amount: $433,125 | Activity Code: R35 | Study Section: Special Emphasis Panel[ZRG1 CDB-E (55)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11260695