Cardiac fibrosis is a key physiopathological process underlying the progression of virtually all heart diseases and related conditions, including myocardial infarction, pressure overload, and heart failure. Once regarded as a homogeneous and passive population, cardiac fibroblasts are now recognized as highly heterogeneous and dynamic, comprising distinct subpopulations with specialized molecular and functional identities. These subpopulations include resident fibroblasts, activated myofibroblasts, matrifibrocytes, inflammatory fibroblasts, and senescent fibroblasts, each contributing uniquely to extracellular matrix (ECM) remodeling, cytokine secretion, and intercellular crosstalk. Recent advances in single-cell transcriptomics, lineage tracing, and epigenetic profiling have revealed the plasticity and phenotypic transitions of cardiac fibroblasts in both physiological and pathological contexts. This review synthesizes current knowledge on fibroblast diversity in the adult heart, including their embryological origins and anatomical distribution, and explores how these insights could guide the development of precision anti-fibrotic therapies. We discuss a selection of emerging therapeutic strategies, including subtype-specific targeting (e.g., anti-POSTN, anti-IL1β), modulation of key signaling pathways (e.g., TGF-β, Wnt, Notch), with a brief mention also of novel approaches based on non-coding RNAs and epigenetic regulators. A better understanding of cardiac fibroblast heterogeneity holds significant potential for the design of more specific cell-type and context-tailored interventions, moving toward more effective and personalized treatments for cardiac fibrosis and its sequelae.

Fibrosis is a fundamental pathological process driving heart failure progression by promoting extracellular matrix deposition and impairing myocardial compliance. In recent years, the sirtuin family of NAD⁺-dependent deacetylases, traditionally linked to aging and metabolism, has emerged as a key regulator of cardiac fibrotic remodeling. This review investigates the roles of sirtuins in mitigating cardiac fibrosis, with emphasis on mechanisms such as mitochondrial preservation and the therapeutic potential of their modulation. Sirtuin signaling attenuates fibrosis by regulating intracellular pathways that control fibroblast activation. In particular, sirtuin-mediated deacetylation modulates pro-fibrotic mediators, including the TGF-β/Smad pathway, thereby reducing collagen synthesis and fibrotic gene expression. However, their effects are isoform- and context-dependent: SIRT1, SIRT3, SIRT6, and SIRT7 generally exert protective roles, whereas SIRT2 and SIRT5 may display neutral or even pro-fibrotic actions depending on the cell type, disease stage, and experimental context. Recognizing this complexity is essential to evaluate their therapeutic relevance. Building on these mechanistic insights, the review explores the preclinical development of sirtuin-targeted therapies. Strategies include NAD⁺ precursors, natural compounds, novel small-molecule activators with enhanced specificity, and agents that indirectly stimulate sirtuins through metabolic modulation. Such approaches highlight the potential of pharmacologically enhancing sirtuin activity to counteract maladaptive cardiac remodeling and improve outcomes in heart failure. By integrating molecular insights with advances in pharmacology, this review synthesizes the most recent mechanistic findings from the past three years with a dedicated focus on the translational challenges and opportunities of pharmacologically targeting sirtuins for anti-fibrotic therapy.

Background: Cardiometabolic syndromes, including diabetes, obesity, and metabolic syndrome, significantly contribute to cardiovascular fibrosis, a major driver of heart failure. Non-coding RNAs (ncRNAs)—notably microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs)—have emerged as critical epigenetic regulators of fibrotic remodeling. Recent studies indicate that widely used metabolic modulators can influence ncRNA expression, potentially impacting on cardiovascular fibrosis. This review synthesizes evidence on the interplay between metabolic therapies and ncRNA regulation, with emphasis on therapeutic and biomarker potential of miRNAs. Methods: A literature search was manually curated and conducted on PubMed for studies published mainly in the last decade and evaluating the effects of metformin, sodium-glucose cotransporter-2 (SGLT2) inhibitors, peroxisome proliferator-activated receptor gamma (PPARγ) agonists, glucagon-like peptide 1 (GLP-1) receptor agonists, and fatty acid oxidation inhibitors on ncRNA expression in the context of cardiovascular fibrosis. Data from in vitro, in vivo, and clinical studies were extracted and categorized by drug class, ncRNA target, and functional outcomes. Results: Several metabolic modulators specifically downregulate pro-fibrotic (miR-21, miR-92, H19, and metastasis associated lung adenocarcinoma transcript 1 (MALAT1)) and upregulate anti-fibrotic ncRNAs (miR-29, miR-133a, miR-711, miR-133a, miR-30a and miR-200 family). This results in global attenuation of the transforming growth factor- beta (TGF-β) signaling, which limits extracellular matrix (ECM) accumulation thus improving myocardial compliance. Across drug classes, changes in ncRNA profiles paralleled improvements in fibrosis-related endpoints. Conclusions: Metabolic modulators exert anti-fibrotic effects partly through ncRNA regulation, offering novel therapeutic strategies and potential biomarkers for cardiovascular fibrosis in cardiometabolic disease. Targeting metabolic–ncRNA crosstalk may enable more precise and synergistic interventions for preventing or reversing pathological remodeling.

Radiotherapy-induced cardiac toxicity and consequent diseases still represent potential severe late complications for many cancer survivors who undergo therapeutic thoracic irradiation. We aimed to assess the phenotypic and paracrine features of resident cardiac mesenchymal stromal cells (CMSCs) at early follow-up after the end of thoracic irradiation of the heart as an early sign and/or mechanism of cardiac toxicity anticipating late organ dysfunction. Resident CMSCs were isolated from a rat model of fractionated thoracic irradiation with accurate and clinically relevant heart dosimetry that developed delayed dose-dependent cardiac dysfunction after 1 year. Cells were isolated 6 and 12 weeks after the end of radiotherapy and fully characterized at the transcriptional, paracrine, and functional levels. CMSCs displayed several altered features in a dose- and time-dependent trend, with the most impaired characteristics observed in those exposed in situ to the highest radiation dose with time. In particular, altered features included impaired cell migration and 3D growth and a and significant association of transcriptomic data with GO terms related to altered cytokine and growth factor signaling. Indeed, the altered paracrine profile of CMSCs derived from the group at the highest dose at the 12-week follow-up gave significantly reduced angiogenic support to endothelial cells and polarized macrophages toward a pro-inflammatory profile. Data collected in a clinically relevant rat model of heart irradiation simulating thoracic radiotherapy suggest that early paracrine and transcriptional alterations of the cardiac stroma may represent a dose- and time-dependent biological substrate for the delayed cardiac dysfunction phenotype observed in vivo.

Cancer alters both local and distant tissue by influencing the microenvironment. In this regard, the interplay with the stromal fraction is considered critical as this latter can either foster or hamper the progression of the disease. Accordingly, the modality by which tumors may alter distant niches of stromal cells is still unclear, especially at early stages. In this short report, we attempt to better understand the biology of this cross-talk. In our autologous stromal experimental setting, we found that remote adipose tissue-derived mesenchymal stem cells (mediastinal AMSC) obtained from patients with lung adenocarcinoma sustain proliferation and clonogenic ability of A549 and human primary lung adenocarcinoma cells similarly to the autologous stromal lung counterpart (LMSC). This effect is not observed in lung benign diseases such as the hamartochondroma. This finding was validated by conditioning benign AMSC with supernatants from LAC for up to 21days. The new reconditioned media of the stromal fraction so obtained, was able to increase cell proliferation of A549 cells at 14 and 21days similar to that derived from AMSC of patients with lung adenocarcinoma. The secretome generated by remote AMSC revealed overlapping to the corresponding malignant microenvironment of the autologous local LMSC. Among the plethora of 80 soluble factors analyzed by arrays, a small pool of 5 upregulated molecules including IL1-β, IL-3, MCP-1, TNF-α, and EGF, was commonly shared by both malignant-like autologous A- and L-MSC derived microenvironments vs those benign. The bioinformatics analysis revealed that these proteins were strictly and functionally interconnected to lung fibrosis and proinflammation and that miR-126, 101, 486, and let-7-g were their main targets. Accordingly, we found that in lung cancer tissues and blood samples from the same set of patients here employed, miR-126 and miR-486 displayed the highest expression levels in tissue and blood, respectively. When the miR-126-3p was silenced in A549 treated with AMSC-derived conditioned media from patients with lung adenocarcinoma, cell proliferation decreased compared to control media.

Charme is a murine long non-coding RNA necessary for the embryonic development of the heart. In vivo Charme knock-out causes prominent alterations of tissue structure, due to cardiac hyperplasia, and leads to the development of cardiac dysfunctions. Cardiac fibroblasts (CFs) play pivotal roles in both the development and homeostatic maintenance of the cardiac tissue, and the effect of Charme depletion on this cell compartment has not been addressed. This study investigated the phenotype and function of resident CFs isolated from Charme knockout (Charme ^KO ) mice and revealed their impaired maturation and functionality. Charme ^KO hearts show decreased levels of collagen I content in the extracellular matrix, associated with reduced extracellular matrix-related gene expression and matrix remodeling ability of CFs. Charme ^KO CFs show impaired phenotypic conversion into myofibroblasts and reduced responsiveness to activation stimuli, accompanied by the retention of features proper of unactivated mesenchymal cells. Charme depletion also affects CF paracrine function, determining an impoverishment in cardioprotective cytokines in their secretome, with consequent reduced ability to mediate PI3K/Akt pathway activation in cardiomyocytes and to induce the angiogenic process in endothelial cells. Charme ^KO CFs also proved to be less supportive of cardiomyocyte maturation in an in vitro model of cardiac differentiation, thus indicating a potential contribution to the impairment of cardiomyocyte maturation in vivo. Overall, the evidence collected suggests that Charme depletion in the heart impairs CF maturation capacity and ECM deposition function, which can contribute to the alterations observed in the Charme ^KO mice. These findings pave the way to deeper investigations on the intercellular signaling occurring in the heart upon Charme ablation to identify how microenvironment homeostasis contributes to cardiomyocyte maturation and is potentially involved in cardiac diseases.