In a transformative breakthrough that may reshape our understanding of obesity-related inflammation, researchers have uncovered a pivotal molecular mechanism involving Sirt6 deficiency in mast cells that exacerbates adipose tissue fibroinflammation. This discovery, detailed in a recent publication in Nature Communications, illuminates the complex interplay between immune cells and fat tissue, identifying galectin-3 signaling as the critical conduit driving inflammatory and fibrotic processes within the adipose microenvironment during obesity.
Obesity is widely recognized not merely as a state of excess fat accumulation but as a chronic, low-grade inflammatory condition with profound implications for metabolic health. Adipose tissue inflammation is a major contributor to insulin resistance, type 2 diabetes, and cardiovascular disease. Despite extensive research, the cellular and molecular underpinnings that fuel this persistent adipose dysfunction remain elusive. The study led by Song et al. focuses on the epigenetic regulator Sirt6 and its impact on mast cells—immune cells traditionally linked to allergic responses but increasingly appreciated for their roles in metabolic regulation and tissue remodeling.
Sirt6, a member of the sirtuin family of NAD+-dependent deacetylases, is known for its regulatory functions in chromatin remodeling, DNA repair, and metabolic homeostasis. Emerging evidence has highlighted its influence on inflammation and aging, but its role in mast cells within adipose tissue had not been elucidated until now. By using genetically engineered mouse models and advanced molecular tools, the research team demonstrated that the absence of Sirt6 in mast cells precipitates an aberrant activation state, leading to enhanced secretion of pro-fibrotic and pro-inflammatory mediators.
Central to this pathological process is galectin-3, a β-galactoside-binding lectin implicated in various immune and fibrotic responses. The study revealed that Sirt6-deficient mast cells exhibit upregulated galectin-3 expression, which acts as a signaling nexus, amplifying inflammatory cascades and promoting fibrotic remodeling in adipose tissues. Notably, galectin-3’s interaction with extracellular matrix components and cell surface receptors orchestrates a feed-forward loop that sustains inflammation and fibrosis, thereby impairing adipocyte function and insulin sensitivity.
The research employed comprehensive histological analyses, flow cytometry, and transcriptomic profiling to dissect the inflammatory milieu fostered by Sirt6 deficiency. These evaluations underscored a robust infiltration of inflammatory cells, increased collagen deposition, and fibrotic gene signatures, all hallmarks of dysfunctional adipose tissue architecture. Crucially, interventions that inhibited galectin-3 signaling ameliorated these pathological features, underscoring the therapeutic potential of targeting this pathway in obesity-related metabolic dysfunction.
These findings have far-reaching implications, extending beyond fundamental science into translational and clinical paradigms. By establishing mast-cell Sirt6 as a critical regulator of adipose tissue homeostasis, the study opens new avenues for innovative obesity treatments aimed at curbing fibroinflammatory processes. Pharmacological enhancement of Sirt6 activity or galectin-3 blockade may emerge as promising strategies to restore adipose tissue integrity and improve metabolic outcomes.
Moreover, the elucidation of this mast cell–galectin-3 axis provides insight into the cellular crosstalk that drives chronic inflammation in obesity, a process previously attributed predominantly to macrophages and adipocytes. Recognizing mast cells as active participants and regulators within adipose tissue redefines the immunometabolic landscape and compels a re-examination of immune interventions in metabolic diseases.
The study also highlights the intricate balance between immune regulatory factors and extracellular matrix remodeling proteins, emphasizing how epigenetic regulators such as Sirt6 intricately modulate these processes. These insights into the epigenetic orchestration of inflammation and fibrosis challenge the conventional paradigms and lay the groundwork for epigenetic therapies tailored to metabolic disorders.
Furthermore, this investigation exemplifies the power of integrative research methodologies, combining genetic mouse models with molecular assays and bioinformatics to unravel complex disease mechanisms. The meticulous approach employed by Song and colleagues ensures robustness and reproducibility, enhancing the translational relevance of their discoveries.
Obesity remains a global health crisis with multifactorial causes and consequences, and its associated adipose tissue inflammation stands as a stumbling block to effective treatment. The identification of Sirt6 deficiency in mast cells as a trigger for galectin-3-mediated fibroinflammation marks a milestone in deciphering the immune-metabolic interface, providing a compelling target for intervention in obesity and its metabolic sequelae.
Future research prompted by these findings may explore the broader implications of Sirt6 modulation in other immune cell types and tissues affected by fibrotic diseases. In addition, clinical studies will be essential to evaluate the safety and efficacy of potential therapies aimed at restoring Sirt6 function or inhibiting galectin-3, with the goal of translating these mechanistic insights into tangible health benefits.
The discovery also encourages a holistic view of obesity pathogenesis that integrates epigenetic factors, immune cell heterogeneity, and extracellular matrix dynamics. This comprehensive perspective enhances our understanding of how chronic inflammation evolves and persists in adipose tissue, potentially reshaping approaches to metabolic disorder management.
As research continues to uncover the nuanced interactions within the adipose tissue microenvironment, the role of mast cells and their epigenetic regulation emerges as a vital piece of the puzzle. The work of Song and colleagues not only advances the frontiers of obesity biology but also reinforces the imperative to investigate immune-epigenetic networks in chronic inflammatory diseases.
In conclusion, the identification of Sirt6 deficiency in mast cells as a driver of adipose tissue inflammation and fibrosis via galectin-3 signaling marks a paradigm shift in obesity research. This innovative study positions mast cell epigenetic regulation at the heart of metabolic inflammation, providing a novel therapeutic target that could change the landscape of obesity treatment and improve outcomes for millions worldwide.
Subject of Research: The role of Sirt6 deficiency in mast cells promoting adipose fibroinflammation in obesity through galectin-3 signaling.
Article Title: Sirt6 deficiency in mast cells promotes adipose fibroinflammation in obesity through galectin-3 signaling.
Article References:
Song, MY., Jeon, Y.G., Do Yang, J. et al. Sirt6 deficiency in mast cells promotes adipose fibroinflammation in obesity through galectin-3 signaling. Nat Commun 17, 57 (2026). https://doi.org/10.1038/s41467-025-66040-z
Image Credits: AI Generated
DOI: https://doi.org/10.1038/s41467-025-66040-z
Tags: cardiovascular disease and obesitychronic inflammation and insulin resistanceepigenetic regulators in obesityfibroinflammation in fat tissuesgalectin-3 signaling in obesityinflammation in adipose tissuemast cells and metabolic regulationmetabolic implications of obesityNAD+-dependent deacetylases in health.Sirt6 and immune cell interactionSirt6 deficiency and obesitytype 2 diabetes and inflammation
