STIM1-mediated Treg instability in HFpEF: a new immunological target emerges?

Abstract

Heart failure with preserved ejection fraction (HFpEF) accounts for nearly half of all heart failure cases and remains a major unmet clinical challenge. Increasing evidence supports the view of HFpEF as a systemic inflammatory syndrome driven by aging and cardiometabolic comorbidities, including obesity, hypertension, and chronic kidney disease. Within this framework, regulatory T cells (Tregs), which are essential for maintaining immune tolerance and limiting excessive inflammation, have emerged as important modulators of disease progression. However, the mechanisms underlying Treg dysfunction in HFpEF have remained poorly understood. In this issue, Srinivas et al. identify stromal interaction molecule 1 (STIM1)-dependent calcium signaling as a critical regulator of Treg instability in HFpEF. The authors show that patients with HFpEF exhibit reduced circulating Treg numbers, increased STIM1 expression, and activation of endoplasmic reticulum stress, apoptotic, and inflammatory pathways. Using a cardiometabolic murine model and Treg-specific STIM1 knockout mice, they establish a causal role for Treg-intrinsic STIM1 signaling in disease development. These findings position STIM1 as a molecular link between cardiometabolic stress, immune dysregulation, and cardiac remodeling. They further support the concept that immune-cell plasticity is a major determinant of HFpEF pathogenesis and suggest that preserving Treg stability may represent a novel therapeutic strategy. Although important questions remain regarding disease timing, clinical translation, and sex-specific effects, this work advances our understanding of HFpEF as an immune-mediated disorder and identifies STIM1-dependent calcium signaling as a promising therapeutic target.

Heart failure remains a leading cause of morbidity and mortality worldwide, and despite substantial advances in pharmacological and device-based therapies, improvements in outcomes have been modest. Heart failure with preserved ejection fraction (HFpEF) now accounts for approximately half of all heart failure cases and carries a prognosis comparable to that of heart failure with reduced ejection fraction (HFrEF) [2, 3]. Yet, unlike HFrEF, HFpEF lacks effective targeted therapies, reflecting an incomplete understanding of its complex and multifactorial pathophysiology.

Over the past decade, HFpEF has increasingly been recognized not simply as a cardiac disorder, but as a systemic syndrome driven by chronic inflammation and metabolic stress associated with aging and common comorbidities such as obesity, hypertension, and chronic kidney disease [4, 5]. Within this evolving framework, immune dysregulation has emerged as a central contributor to disease progression. Growing attention has focused on the role of adaptive immune cells and their contribution to persistent low-grade inflammation. Regulatory T cells (Tregs), a specialized subset of CD4⁺ T cells characterized by expression of the transcription factor Foxp3, are essential for maintaining immune tolerance and limiting excessive inflammation [6]. Tregs are present but are not the dominant immune signal in HFpEF [7]; compared with other immune cells, strongly associated with HFpEF such as monocytes/macrophages or neutrophils considered as pro-inflammatory/pro-fibrotic drivers, Tregs appear relatively reduced or functionally imbalanced and likely protective when preserved [8]. Although alterations in Treg abundance and function have been reported in HFpEF [9], the mechanisms responsible for their dysfunction have remained largely unknown.

In this issue, Srinivas and colleagues [1] provide important insight by identifying stromal interaction molecule 1 (STIM1)-dependent calcium as a key regulator of Treg dysfunction in HFpEF. Their study suggests that the loss of Treg stability -associated to altered calcium homeostasis [10]-, fosters a pro-inflammatory immune environment that may contribute directly to disease progression. The authors report that patients with HFpEF exhibit reduced circulating Treg numbers, consistent with previous observations [9], together with increased STIM1 expression and activation of stress-related pathways, including endoplasmic reticulum stress, apoptosis, and inflammatory signaling. Collectively, these findings support the concept of “Treg instability,” a state in which Tregs progressively lose their lineage-defining characteristics and suppressive capacity under chronic stress conditions.

Treg stability, defined by sustained Foxp3 expression and preservation of a controlled immune-suppressive function, is essential for preventing immune-mediated tissue injury. However, under pathological conditions, Tregs can undergo phenotypic and functional reprogramming losing Foxp3 expression and acquiring effector-like properties. This process is regulated by a complex interplay of metabolic signals, epigenetic modifications, and transcriptional networks that are shaped by the inflammatory microenvironment [11]. In this context, the identification of STIM1-dependent calcium signaling as a determinant of Treg fate represents an important advance in our understanding of immune regulation in HFpEF (Fig. 1A). Notably, previous work from the same group demonstrated that selective deletion of STIM1 in Tregs protects against other forms of cardiovascular disease [12, 13], further supporting a central role for STIM1 in controlling Treg stability and function.

Fig. 1.

HFpEF phenotype is associated to STIM1-dependent Treg dysfunction. A Tregs phenotypic switch during HFpEF. Upon HFpEF, Tregs suffer a decrease in Foxp3 expression which is associated to a dysfunctional phenotype, which can be prevented in mice by ablating Stim1 in Tregs. B HFpEF-protective traits associated to Treg-specificStim1ablation. Treg^Stim1−/− mice blunt or do not develop HFpEF-specific hallmarks like (i) organ-specific insults associated to HFpEF (e.g.: cardiac diastolic dysfunction, endothelial dysfunction and kidney injury) and (ii) general systemic features (e.g.: cardiovascular fibrotic and inflammatory processes or cellular stress). ER, endoplasmic reticulum; HFpEF, heart failure with preserved ejection fraction; Tregs, regulatory T cells

A major strength of the study is that it moves beyond association to establish causality. Using a well-characterized murine model of cardiometabolic HFpEF [14], the investigators employed Treg-specific STIM1 knockout mice to precisely dissect immune-cell-intrinsic mechanisms. Strikingly, deletion of STIM1 in Tregs protected against hallmark features of HFpEF, positioning Treg-intrinsic STIM1 signaling as a driver of disease pathology (Fig. 1B). At first glance, these findings appear difficult to reconcile with prior evidence showing that STIM1 deficiency impairs Treg function and leads to lymphoproliferation, splenomegaly, and autoimmune manifestations [15]. However, this apparent contradiction may instead highlight the context-dependent nature of STIM1 signaling in Treg biology. Whereas global or developmental STIM1 deficiency disrupts Treg homeostasis and compromises immune tolerance, selective deletion of STIM1 within Tregs in the setting of chronic cardiometabolic stress may prevent maladaptive activation and stress-induced dysfunction. Rather than representing opposing observations, these studies suggest a dual role for STIM1: indispensable for maintaining basal Treg function under physiological conditions, yet potentially deleterious when sustained calcium signaling drives Treg instability during chronic inflammatory disease.

Mechanistically, Srinivas et al. [1] provide compelling evidence that STIM1 signaling reshapes Treg identity. Upon in vitro metabolic stress conditions mimicking in vivo HFpEF conditions, Tregs acquire effector-like features comparable to the treatment with inflammatory mediators (e.g. IL-17 and IFN-γ). This phenotypic transition appears to influence cardiomyocyte inflammatory markers, effectively converting Tregs from guardians of immune homeostasis into contributors to inflammation. By contrast, STIM1-deficient Tregs maintain a more stable and non-pathogenic phenotype, underscoring the critical role of calcium signaling in determining Treg fate under conditions of metabolic and inflammatory stress.

The translational implications of these findings are considerable. They reinforce the emerging concept that immune-cell plasticity, rather than simply immune-cell activation, is a key determinant of chronic inflammatory disorders such as HFpEF. Furthermore, they identify STIM1 as a molecular nexus linking cardiometabolic stress to immune dysfunction. Given the ubiquitous role of calcium signaling across multiple tissues, broad inhibition of STIM1 would likely carry significant risks. Therapeutic approaches in this line would therefore need to achieve cell-type specificity. One intriguing possibility is the adoptive transfer of ex vivo expanded, functionally stable Tregs lacking STIM1, an approach that could circumvent intrinsic defects in endogenous Tregs and restore immune homeostasis. More broadly, strategies aimed at preserving Treg stability may represent a novel immunomodulatory avenue in HFpEF.

The study also raises several important questions. Whether STIM1-driven Treg dysfunction represents an initiating event in HFpEF or arises secondarily to systemic inflammation remains unclear. Similarly, it will be important to determine whether modulation of calcium-signaling pathways can reverse established disease and translate into meaningful clinical benefit. Given the remarkable heterogeneity of HFpEF, identifying patient subsets most likely to benefit from immune-targeted therapies will be essential for future clinical translation.

An additional limitation deserves consideration. The preclinical studies were performed exclusively in male mice. This is particularly relevant because HFpEF is more prevalent in women and exhibits significant sex-specific differences in immune responses, hormonal regulation, vascular function, and cardiac remodeling. The absence of female cohorts limits the generalizability of the findings and leaves unresolved the potential influence of sex hormones on STIM1-dependent calcium signaling and Treg biology. Future studies incorporating both sexes will therefore be critical to determine whether these mechanisms are universally conserved and whether therapeutic strategies targeting STIM1 can be broadly applied across the diverse HFpEF population.

Overall, the work by Srinivas et al. [1] advances the growing view of HFpEF as an immune-mediated disease and provides a unifying mechanism linking cardiometabolic stress, immune dysregulation, and disease progression. By identifying STIM1-dependent calcium signaling as a key driver of Treg instability, the authors open new avenues for immune-directed therapies. More broadly, their findings underscore the importance of immune-cell resilience in maintaining cardiovascular health and suggest that restoring immune homeostasis may represent a promising therapeutic strategy for HFpEF and other chronic inflammatory cardiovascular disorders. Future investigations should move beyond defining STIM1 as a regulator of Treg biology toward establishing how manipulation of this pathway can be safely and effectively harnessed therapeutically. By integrating mechanistic immunology, systems biology, and translational studies, the field may ultimately determine whether restoring Treg stability can alter the natural history of HFpEF, a condition that remains one of the greatest unmet needs in contemporary cardiovascular medicine.

Author contributions

AP and AB-R have written the manuscript.

Funding

This work was supported by Grant PID2024-156673OB-I00 and PID2021-122941OB-I00 funded by MCIN/AEI/10.13039/5011000110333, ‘ERDF A way of making Europe’, Sociedad Española de Cardiología and AGAUR Generalitat de Catalunya (2021-SGR-01437).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.