---
title: "Lactate’s Dual Immunometabolic Roles in the Inflammatory Microenvironment"
id: "pubmed-42900005"
canonical_url: "https://medichelpline.com/clinical-feed/pubmed-42900005"
content_type: "clinical_feed_article"
specialty: "Critical Care"
source_name: "PubMed / NCBI"
source_url: "https://pubmed.ncbi.nlm.nih.gov/42900005/"
doi: "10.1111/imm.70215"
published_at: "2026-10-20T00:00:00.000Z"
evidence_level: "Journal Article"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Lactate’s Dual Immunometabolic Roles in the Inflammatory Microenvironment
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/pubmed-42900005
- **Specialty:** [Critical Care](https://medichelpline.com/clinical-feed/critical-care.md)
- **Primary Source:** PubMed / NCBI
- **Source URL:** [Original Journal Publication](https://pubmed.ncbi.nlm.nih.gov/42900005/)
- **DOI:** [10.1111/imm.70215](https://doi.org/10.1111%2Fimm.70215)
- **Published At:** 2026-10-20T00:00:00.000Z
- **Evidence Rating:** Journal Article
## Executive GIST (TL;DR)
- The review frames **lactate** not as a waste product but as an active **immunometabolic regulator** that shapes inflammation across contexts. - Authors argue lactate acts as a context-dependent rheostat; its effects depend on four integrated factors: lactate concentration, cellular identity, disease stage and the local **inflammatory microenvironment**. - Mechanisms covered include metabolic reprogramming, intercellular lactate shuttling, receptor-mediated signalling, intracellular sensing and protein lactylation; these processes collectively regulate immune activation and resolution. - The paper summarises cell-specific effects observed in endothelial cells, macrophages, fibroblast-like synoviocytes, neutrophils and lymphocytes, showing divergent functional outcomes across cell types. - Representative disease models discussed include **rheumatoid arthritis**, **sepsis** and **atherosclerosis**, with emphasis on how lactate’s role varies by disease context and stage. - Therapeutic strategies evaluated target lactate production, transport, sensing and metabolism; the authors caution against blanket lactate inhibition and advocate context-specific modulation. - The review notes incomplete understanding of the duality mechanisms, which limits development of effective lactate-targeted therapies and leaves open specific mechanistic and translational questions.
## Clinical Analysis & Structured Key Points
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Online ahead of print. # Yin-Yang: The Dual Role of Lactate as a Context-Dependent Immunometabolic Regulator in the Inflammatory Microenvironment [Shihan Wang](https://pubmed.ncbi.nlm.nih.gov/?term=Wang+S&cauthor_id=42900005)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42900005/#full-view-affiliation-1 "College of Pharmacy, Anhui University of Chinese Medicine, Hefei, China.")[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42900005/#full-view-affiliation-2 "Key Laboratory of Xin'an Medicine, Ministry of Education, Anhui University of Chinese Medicine, Hefei, China.")[ 3 ](https://pubmed.ncbi.nlm.nih.gov/42900005/#full-view-affiliation-3 "Anhui Provincial Key Laboratory of Chinese Medicinal Formula, Hefei, China."), [Peirong Gan](https://pubmed.ncbi.nlm.nih.gov/?term=Gan+P&cauthor_id=42900005)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42900005/#full-view-affiliation-1 "College of Pharmacy, Anhui University of Chinese Medicine, Hefei, China.")[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42900005/#full-view-affiliation-2 "Key Laboratory of Xin'an Medicine, Ministry of Education, Anhui University of Chinese Medicine, Hefei, China.")[ 3 ](https://pubmed.ncbi.nlm.nih.gov/42900005/#full-view-affiliation-3 "Anhui Provincial Key Laboratory of Chinese Medicinal Formula, Hefei, China."), [Ya Chen](https://pubmed.ncbi.nlm.nih.gov/?term=Chen+Y&cauthor_id=42900005)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42900005/#full-view-affiliation-1 "College of Pharmacy, Anhui University of Chinese Medicine, Hefei, China.")[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42900005/#full-view-affiliation-2 "Key Laboratory of Xin'an Medicine, Ministry of Education, Anhui University of Chinese Medicine, Hefei, China.")[ 3 ](https://pubmed.ncbi.nlm.nih.gov/42900005/#full-view-affiliation-3 "Anhui Provincial Key Laboratory of Chinese Medicinal Formula, Hefei, China."), [Beibei Yang](https://pubmed.ncbi.nlm.nih.gov/?term=Yang+B&cauthor_id=42900005)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42900005/#full-view-affiliation-1 "College of Pharmacy, Anhui University of Chinese Medicine, Hefei, China.")[ 3 ](https://pubmed.ncbi.nlm.nih.gov/42900005/#full-view-affiliation-3 "Anhui Provincial Key Laboratory of Chinese Medicinal Formula, Hefei, China."), [Tao Ding](https://pubmed.ncbi.nlm.nih.gov/?term=Ding+T&cauthor_id=42900005)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42900005/#full-view-affiliation-1 "College of Pharmacy, Anhui University of Chinese Medicine, Hefei, China.")[ 3 ](https://pubmed.ncbi.nlm.nih.gov/42900005/#full-view-affiliation-3 "Anhui Provincial Key Laboratory of Chinese Medicinal Formula, Hefei, China."), [Hong Wu](https://pubmed.ncbi.nlm.nih.gov/?term=Wu+H&cauthor_id=42900005)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42900005/#full-view-affiliation-1 "College of Pharmacy, Anhui University of Chinese Medicine, Hefei, China.")[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42900005/#full-view-affiliation-2 "Key Laboratory of Xin'an Medicine, Ministry of Education, Anhui University of Chinese Medicine, Hefei, China.")[ 3 ](https://pubmed.ncbi.nlm.nih.gov/42900005/#full-view-affiliation-3 "Anhui Provincial Key Laboratory of Chinese Medicinal Formula, Hefei, China.") Affiliations Expand ### Affiliations * 1 College of Pharmacy, Anhui University of Chinese Medicine, Hefei, China. * 2 Key Laboratory of Xin'an Medicine, Ministry of Education, Anhui University of Chinese Medicine, Hefei, China. * 3 Anhui Provincial Key Laboratory of Chinese Medicinal Formula, Hefei, China. * PMID: **42900005** * DOI: [ 10.1111/imm.70215 ](https://doi.org/10.1111/imm.70215) Item in Clipboard Review # Yin-Yang: The Dual Role of Lactate as a Context-Dependent Immunometabolic Regulator in the Inflammatory Microenvironment Shihan Wang et al. Immunology. 2026. Show details Display options Display options Format Abstract PubMed PMID Immunology Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Immunology%22%5Bjour%5D&sort=date&sort_order=desc) * [ Search in NLM Catalog ](https://www.ncbi.nlm.nih.gov/nlmcatalog?term=%22Immunology%22%5BTitle+Abbreviation%5D) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42900005/) . 2026 Oct 20. doi: 10.1111/imm.70215. Online ahead of print. ### Authors [Shihan Wang](https://pubmed.ncbi.nlm.nih.gov/?term=Wang+S&cauthor_id=42900005)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42900005/#short-view-affiliation-1 "College of Pharmacy, Anhui University of Chinese Medicine, Hefei, China.")[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42900005/#short-view-affiliation-2 "Key Laboratory of Xin'an Medicine, Ministry of Education, Anhui University of Chinese Medicine, Hefei, China.")[ 3 ](https://pubmed.ncbi.nlm.nih.gov/42900005/#short-view-affiliation-3 "Anhui Provincial Key Laboratory of Chinese Medicinal Formula, Hefei, China."), [Peirong Gan](https://pubmed.ncbi.nlm.nih.gov/?term=Gan+P&cauthor_id=42900005)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42900005/#short-view-affiliation-1 "College of Pharmacy, Anhui University of Chinese Medicine, Hefei, China.")[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42900005/#short-view-affiliation-2 "Key Laboratory of Xin'an Medicine, Ministry of Education, Anhui University of Chinese Medicine, Hefei, China.")[ 3 ](https://pubmed.ncbi.nlm.nih.gov/42900005/#short-view-affiliation-3 "Anhui Provincial Key Laboratory of Chinese Medicinal Formula, Hefei, China."), [Ya Chen](https://pubmed.ncbi.nlm.nih.gov/?term=Chen+Y&cauthor_id=42900005)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42900005/#short-view-affiliation-1 "College of Pharmacy, Anhui University of Chinese Medicine, Hefei, China.")[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42900005/#short-view-affiliation-2 "Key Laboratory of Xin'an Medicine, Ministry of Education, Anhui University of Chinese Medicine, Hefei, China.")[ 3 ](https://pubmed.ncbi.nlm.nih.gov/42900005/#short-view-affiliation-3 "Anhui Provincial Key Laboratory of Chinese Medicinal Formula, Hefei, China."), [Beibei Yang](https://pubmed.ncbi.nlm.nih.gov/?term=Yang+B&cauthor_id=42900005)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42900005/#short-view-affiliation-1 "College of Pharmacy, Anhui University of Chinese Medicine, Hefei, China.")[ 3 ](https://pubmed.ncbi.nlm.nih.gov/42900005/#short-view-affiliation-3 "Anhui Provincial Key Laboratory of Chinese Medicinal Formula, Hefei, China."), [Tao Ding](https://pubmed.ncbi.nlm.nih.gov/?term=Ding+T&cauthor_id=42900005)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42900005/#short-view-affiliation-1 "College of Pharmacy, Anhui University of Chinese Medicine, Hefei, China.")[ 3 ](https://pubmed.ncbi.nlm.nih.gov/42900005/#short-view-affiliation-3 "Anhui Provincial Key Laboratory of Chinese Medicinal Formula, Hefei, China."), [Hong Wu](https://pubmed.ncbi.nlm.nih.gov/?term=Wu+H&cauthor_id=42900005)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42900005/#short-view-affiliation-1 "College of Pharmacy, Anhui University of Chinese Medicine, Hefei, China.")[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42900005/#short-view-affiliation-2 "Key Laboratory of Xin'an Medicine, Ministry of Education, Anhui University of Chinese Medicine, Hefei, China.")[ 3 ](https://pubmed.ncbi.nlm.nih.gov/42900005/#short-view-affiliation-3 "Anhui Provincial Key Laboratory of Chinese Medicinal Formula, Hefei, China.") ### Affiliations * 1 College of Pharmacy, Anhui University of Chinese Medicine, Hefei, China. * 2 Key Laboratory of Xin'an Medicine, Ministry of Education, Anhui University of Chinese Medicine, Hefei, China. * 3 Anhui Provincial Key Laboratory of Chinese Medicinal Formula, Hefei, China. * PMID: **42900005** * DOI: [ 10.1111/imm.70215 ](https://doi.org/10.1111/imm.70215) Item in Clipboard Cite Display options Display options Format Abstract PubMed PMID Linked Discoveries ## Abstract Lactate, once regarded merely as the terminal product of glycolysis, is now recognised as a pivotal immunometabolic regulator that actively shapes inflammatory responses. However, accumulating evidence reveals an apparent paradox that lactate can either amplify immune activation or promote inflammation resolution depending on the biological context. The mechanisms underlying this functional duality remain incompletely understood, limiting the development of effective lactate-targeted therapies. In this review, we propose that lactate functions as a context-dependent immunometabolic rheostat whose Yin-Yang properties are determined by the integration of four key factors: lactate concentration, cellular identity, disease stage and inflammatory microenvironment. We summarise how lactate regulates immune responses through coordinated control of metabolic reprogramming, intercellular lactate shuttling, receptor-mediated signalling, intracellular sensing, and protein lactylation, thereby orchestrating the activation and resolution of inflammation. We further discuss the cell-specific actions of lactate across endothelial cells, macrophages, fibroblast-like synoviocytes, neutrophils, and lymphocytes, highlighting how these mechanisms collectively remodel the inflammatory microenvironment. Beyond mechanistic insights, we examine evidence from representative inflammatory disease models, including rheumatoid arthritis, sepsis, and atherosclerosis, and evaluate emerging therapeutic strategies targeting lactate production, transport, sensing and metabolism. Rather than advocating indiscriminate lactate inhibition, current evidence supports context-specific modulation of lactate signalling according to disease stage and immune landscape. **Keywords:** Yin‐Yang; bidirectional immune modulation; inflammatory microenvironment; lactate; regulatory molecule. © 2026 John Wiley & Sons Ltd. [PubMed Disclaimer](https://pubmed.ncbi.nlm.nih.gov/disclaimer/) ## References 1. 1. M. G. Netea, F. Balkwill, M. Chonchol, et al., “A Guiding Map for Inflammation,” Nature Immunology 18 (2017): 826–831, . 2. 1. D. Furman, J. Campisi, E. Verdin, et al., “Chronic Inflammation in the Etiology of Disease Across the Life Span,” Nature Medicine 25 (2019): 1822–1832, [https://doi.org/10.1038/s41591‐019‐0675‐0](https://doi.org/10.1038/s41591%E2%80%90019%E2%80%900675%E2%80%900). 3. 1. R. Medzhitov, “Origin and Physiological Roles of Inflammation,” Nature 454 (2008): 428–435, . 4. 1. N. A. Pascalau, A.‐F. Radu, D. C. N. Cseppento, et al., “An Evidence‐Based Update on the Potential Association Between Rheumatoid Arthritis and Lymphangioleiomyomatosis,” Journal of Personalized Medicine 13 (2023): 607, . 5. 1. Z. Zainal, A. A. Rahim, A. K. Radhakrishnan, S. K. Chang, and H. Khaza'ai, “Investigation of the Curative Effects of Palm Vitamin E Tocotrienols on Autoimmune Arthritis Disease In Vivo,” Scientific Reports 9 (2019): 16793, [https://doi.org/10.1038/s41598‐019‐53424‐7](https://doi.org/10.1038/s41598%E2%80%90019%E2%80%9053424%E2%80%907). Show all 90 references ## Publication types * Review Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Review%22%5Bpt%5D&sort=date&sort_order=desc) * [ Search in MeSH ](https://www.ncbi.nlm.nih.gov/mesh?term=Review) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42900005/) ## Grants and funding * [ 82374117/Innovative Research Group Project of the National Natural Science Foundation of China ](https://pubmed.ncbi.nlm.nih.gov/?term=82374117%2FInnovative+Research+Group+Project+of+the+National+Natural+Science+Foundation+of+China%5BGrants+and+Funding%5D&sort=date&sort_order=desc "All articles for grant 82374117/Innovative Research Group Project of the National Natural Science Foundation of China") * [ 81874360/Innovative Research Group Project of the National Natural Science Foundation of China ](https://pubmed.ncbi.nlm.nih.gov/?term=81874360%2FInnovative+Research+Group+Project+of+the+National+Natural+Science+Foundation+of+China%5BGrants+and+Funding%5D&sort=date&sort_order=desc "All articles for grant 81874360/Innovative Research Group Project of the National Natural Science Foundation of China") * [ 81473400/Innovative Research Group Project of the National Natural Science Foundation of China ](https://pubmed.ncbi.nlm.nih.gov/?term=81473400%2FInnovative+Research+Group+Project+of+the+National+Natural+Science+Foundation+of+China%5BGrants+and+Funding%5D&sort=date&sort_order=desc "All articles for grant 81473400/Innovative Research Group Project of the National Natural Science Foundation of China") * [ KJ2021ZD0060/Key Research Initiatives in Natural Sciences for Anhui Provincial Universities ](https://pubmed.ncbi.nlm.nih.gov/?term=KJ2021ZD0060%2FKey+Research+Initiatives+in+Natural+Sciences+for+Anhui+Provincial+Universities%5BGrants+and+Funding%5D&sort=date&sort_order=desc "All articles for grant KJ2021ZD0060/Key Research Initiatives in Natural Sciences for Anhui Provincial Universities") * [ gxbjZD2022026/Talent Excellence Program of Anhui Provincial Higher Education Institutions ](https://pubmed.ncbi.nlm.nih.gov/?term=gxbjZD2022026%2FTalent+Excellence+Program+of+Anhui+Provincial+Higher+Education+Institutions%5BGrants+and+Funding%5D&sort=date&sort_order=desc "All articles for grant gxbjZD2022026/Talent Excellence Program of Anhui Provincial Higher Education Institutions") [x] Cite Copy Download .nbib .nbib Format: AMA APA MLA NLM **Send To** * [Clipboard](https://pubmed.ncbi.nlm.nih.gov/42900005/) * [Email](https://account.ncbi.nlm.nih.gov/?back_url=https%3A%2F%2Fpubmed.ncbi.nlm.nih.gov%2F42900005%2F%23open-email-panel) * [Save](https://pubmed.ncbi.nlm.nih.gov/42900005/) * [My Bibliography](https://account.nc
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