Pathological cardiac fibrosis is a central hallmark of chronic heart failure, characterized by the maladaptive transformation of quiescent cardiac fibroblasts (CFs) into α-smooth muscle actin (α-SMA)-expressing myofibroblasts. This phenotypic shift drives the excessive accumulation of extracellular matrix proteins, which significantly impairs ventricular compliance and cardiac function. Previous studies have established the unfolded protein response (UPR) as a conserved cellular stress-response pathway involved in restoring endoplasmic reticulum (ER) proteostasis, yet its direct contributions to the fibrotic transcriptional machinery in the heart are not fully elucidated.

A new study in Genes & Diseases by researchers from The First Affiliated Hospital of Zhengzhou University and Tiantan Hospital Henan Brain Hospital identified Xbp1s, the transcriptionally active spliced form of Xbp1 generated during the UPR, as a key regulator of cardiac fibrosis through transcriptional activation of Stat3.

The authors observed increased expression of Xbp1s in fibrotic cardiac tissue and cardiac fibroblasts in mouse models of angiotensin II (Ang II)-induced cardiac fibrosis and pressure-overload heart failure. Fibroblast-specific (cfKO) or myofibroblast-specific (mfKO) Xbp1s deletion markedly reduced cardiac fibrosis, expression of fibrotic markers, and myocardial hypertrophy, while preserving cardiac function following Ang II stimulation. Conversely, myofibroblast-specific Xbp1s overexpression exacerbated fibrotic remodeling and impaired cardiac function.

In vitro experiments further showed that Xbp1s promoted fibroblast-to-myofibroblast transdifferentiation without significantly affecting fibroblast proliferation, indicating that its profibrotic effects are primarily linked to phenotypic activation. Importantly, these effects were attributable specifically to Xbp1s rather than the unspliced Xbp1u isoform, highlighting the functional specificity of the spliced transcription factor.

Mechanistic analyses, including transcriptomic profiling, revealed activation of Stat3-associated pathways following Xbp1s overexpression. Luciferase and ChIP assays demonstrated that Xbp1s physically occupies a conserved UPRE-like sequence in the Stat3 promoter to activate its transcription. This transcriptional regulation promotes a profibrotic gene network that converges on the Stat3–Smad3 signaling axis, suggesting cooperation between the newly identified Xbp1s–Stat3 axis and established TGF-β/Smad signaling in fibrotic remodeling.

Specifically, Xbp1s-mediated Stat3 activation was associated with enhanced phosphorylation of Smad3, significantly amplifying downstream fibrotic signaling. Consistent with this finding, Stat3 expression decreased following Xbp1s deletion and increased with Xbp1s overexpression; similarly, Stat3 depletion or inhibition attenuated Xbp1s-driven fibrosis and reduced downstream Smad3 activation. Genetic depletion of Stat3 also reversed the exacerbated fibrotic phenotype and improved ventricular function in Xbp1s-overexpressing mice.

Overall, this study establishes Xbp1s as a cell-specific transcriptional driver of cardiac fibrosis that promotes fibroblast activation through direct transcriptional activation of Stat3 and subsequent engagement of downstream profibrotic signaling. These findings reveal an important link between cellular stress responses and cardiac fibrotic pathways and identify the Xbp1s–Stat3 axis as a potential therapeutic target for preventing pathological cardiac remodeling and progression toward heart failure.

Reference
Title of the original paper: Xbp1s regulates cardiac fibrosis by transcriptionally activating Stat3 in mice
Journal: Genes & Diseases
Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.
DOI: https://doi.org/10.1016/j.gendis.2026.102276

Funding Information:
National Natural Science Foundation of China (No. 82070233)
Provincial and Ministry Co-constructed Key Projects of Henan Medical Science and Technology (China) (No. SBGJ202302048)
Young and Middle-Aged Health Science and Technology Innovation Talent Project of Henan Province, China (No. JQRC2023010)
Scientific and Technological Project of Henan Province, China (No. 242102310367)
General Program of the Natural Science Foundation of Henan Province, China (No. 262300420174)

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Genes & Diseases publishes rigorously peer-reviewed and high quality original articles and authoritative reviews that focus on the molecular bases of human diseases. Emphasis is placed on hypothesis-driven, mechanistic studies relevant to pathogenesis and/or experimental therapeutics of human diseases. The journal has worldwide authorship, and a broad scope in basic and translational biomedical research of molecular biology, molecular genetics, and cell biology, including but not limited to cell proliferation and apoptosis, signal transduction, stem cell biology, developmental biology, gene regulation and epigenetics, cancer biology, immunity and infection, neuroscience, disease-specific animal models, gene and cell-based therapies, and regenerative medicine.
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