Search Results (379)

Background: Osteoporosis is a multifactorial skeletal disorder characterized by reduced bone mass, impaired bone remodeling, and an increased risk of fractures, particularly under estrogen-deficient conditions. Artocarpus integer (Thunb.) Merr. contains prenylated flavonoids and chalcone derivatives with diverse biological activities; however, its anti-osteoporotic potential remains largely unexplored. This study investigated the phytochemical composition, molecular mechanisms, and anti-osteoporotic effects of A. integer leaf extract in an ovariectomized (OVX) rat model. Methods: Phytochemical profiling was performed using liquid chromatography–high-resolution mass spectrometry (LC–HRMS). Network pharmacology was employed to identify potential osteoporosis-related targets and signaling pathways. The anti-osteoporotic activity of the extract was evaluated in OVX rats through physiological and biochemical assessments, including body weight gain, uterine weight, serum biomarkers, femoral calcium content, and RT-PCR analysis of genes associated with osteogenesis, osteoclastogenesis, and estrogen signaling. Results: LC–HRMS analysis identified several bioactive compounds, including isobavachalcone, artocarpesin, morachalcone A, genistein, apigenin, luteolin, naringenin, catechin derivatives, and mangiferin. Network pharmacology revealed 96 overlapping targets between A. integer phytochemicals and osteoporosis-related genes, highlighting pathways involved in estrogen signaling, PI3K–Akt signaling, osteoclast differentiation, inflammation, and metabolic regulation. In vivo, OVX rats exhibited increased body weight gain, uterine atrophy, elevated leptin levels, reduced adiponectin concentrations, and decreased femoral calcium content. Treatment with A. integer attenuated OVX-induced metabolic alterations, improved adipokine profiles, and increased femoral calcium content, particularly in the medium-dose group. RT-PCR analysis demonstrated the upregulation of the osteogenic markers Runx2 and Osx, together with the downregulation of the osteoclastogenic markers TRAP. Conclusions: Artocarpus integer leaf extract exhibited promising anti-osteoporotic activity through the coordinated regulation of osteogenesis, osteoclastogenesis, estrogen-related signaling, and bone mineral preservation. These findings support the potential development of A. integer as a nutraceutical candidate for the prevention or management of postmenopausal osteoporosis. Full article

Bazedoxifene (BAZ), a selective estrogen receptor modulator, has recently been demonstrated to inhibit the IL-6/STAT3 signaling pathway; however, its direct effects on cardiac fibroblasts and the underlying mechanisms remain unclear. Isoproterenol (ISO)-stimulated Sprague–Dawley neonatal rat cardiac fibroblasts (CFs) were employed as an in vitro model. CCK-8 assay, flow cytometry, Transwell migration assay, ELISA, qRT-PCR, and Western blot were applied to evaluate the effects of BAZ on CF activation, proliferation, migration, and collagen synthesis. Additionally, IL-6 overexpression via lentivirus (Lv-IL-6) was used to assess mediation by IL-6/STAT3 signaling. BAZ (5 μmol/L) significantly inhibited ISO-induced CF proliferation by inducing G₀/G₁ cell-cycle arrest; migration and upregulation of α-SMA and Collagen I/III were reduced; IL-6, TGF-β1, and hydroxyproline concentrations in the conditioned medium were decreased; STAT3 phosphorylation was significantly suppressed. Supplementation with Lv-IL-6 partially reversed these effects. The suppression of ISO-induced CF activation and fibrotic phenotype was associated with inhibition of IL-6 expression and blockade of IL-6/STAT3 signaling, suggesting the involvement of this pathway in the anti-fibrotic effects of BAZ. These findings provide in vitro evidence supporting BAZ as a candidate anti-myocardial fibrosis agent. Full article

Three-dimensional (3D) printing and bioprinting technologies are increasingly used in tissue engineering and in the development of personalized medical devices with tailored biological and mechanical properties. Despite their advantages, these technologies may involve exposure to chemical compounds with uncertain biological effects, including potential endocrine-disrupting activity. This study aims to evaluate the hormonal activity and cytotoxicity of various materials commonly used for 3D printing technologies, including thermoplastics and synthetic materials (PLA, ABS, PCL, b-TPUe, PVA, PEGDA), and biomaterials (collagen, alginate, hyaluronic acid, agarose, silk fibroin, GelMA, HAMA). Hormonal activity was evaluated using the E-screen assay for estrogenic and anti-estrogenic activity, and the PALM assay for androgenic and anti-androgenic activity. Cytotoxic effects are evaluated by assessing cellular metabolic viability using the MTT assay. No detectable estrogenic, anti-estrogenic, androgenic, or anti-androgenic activity, nor any signs of cytotoxicity, were observed within the experimental conditions analysed. This study represents the first analysis of some specific endocrine-related endpoints of a wide range of 3D printing and bioprinting materials, and should not be interpreted as definitive proof of the complete absence of endocrine activity. Further studies addressing additional toxicological parameters and long-term assessments are required to comprehensively characterize their safety and suitability. Full article

Background/Objective: Cinnamaldehyde (CA) is a naturally occurring bioactive compound derived from the leaves, bark, roots, and flowers of the Chinese medicinal plant Cinnamomum cassia. It exhibits a broad spectrum of pharmacological properties, encompassing antioxidant, antibacterial, anti-diabetic, antifungal, and anticancer activities. Notably, it has shown potential therapeutic benefits in the management of type 2 diabetes mellitus (T2DM) and non-alcoholic fatty liver disease (NAFLD). Ochratoxin A (OTA), a common contaminant found in foods such as cereals, coffee, and raisins, is also present in traditional Chinese medicinal materials, including Astragalus and liquorice. T2DM and NAFLD share intertwined pathophysiological pathways, including insulin resistance, dyslipidaemia, chronic low-grade inflammation and oxidative stress, with insulin resistance serving as the common pathological hub for both conditions. Consequently, they frequently co-occur and exacerbate each other. OTA exerts dual-targeted toxicity to the pancreas and liver, which may synergistically drive the development of the comorbidity of T2DM and NAFLD. These two processes are mutually causal and together constitute the pathological basis of metabolic comorbidity. Methods: Network toxicology employs toxicological data, gene expression, and protein–protein interaction (PPI) networks to predict the targets of toxins, while network pharmacology, based on systems biology principles, reveals how drugs exert regulatory effects through multiple targets and pathways. In this study, we employed an integrated network toxicology and network pharmacology approach to jointly decipher the potential mechanisms by which CA intervenes in OTA-induced comorbid T2DM-NAFLD. First, a network toxicology approach was employed to preliminarily screen for core toxicological targets responsible for OTA’s pathogenicity. Subsequently, network pharmacology was used to identify potential targets of CA-mediated intervention in the disease. Finally, the common overlap among the CA intervention targets, OTA toxicity targets, and disease targets was defined as the final set of potential targets for CA-mediated intervention in OTA-induced T2DM-NAFLD comorbidity. A PPI network was constructed using the STRING database, and topological analysis was performed with Cytoscape. Core targets were selected using the median values of six parameters—betweenness centrality, closeness centrality, degree centrality, eigenvector centrality, LAC (local average connectivity) score, and network centrality—as cut-off thresholds, and the top 10 key genes were further identified using the cytoHubba plugin. Gene Ontology (GO) functional enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted via the DAVID database, and the results were visualized on the CNSknowall platform. Lastly, molecular docking of the core targets was performed using the CB-DOCK2 platform to validate binding affinity. Results: Based on an integrated analysis of network toxicology, network pharmacology, and molecular docking, 10 key targets were systematically identified. These may serve as potential mediators of cinnamaldehyde in the treatment of OTA-induced T2DM-NAFLD comorbidity. Among these, six targets—albumin (ALB), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), interleukin-6 (IL-6), tumor necrosis factor (TNF), actin beta (ACTB), and estrogen receptor 1 (ESR1)—possess crystal structures amenable to molecular docking. KEGG enrichment analysis revealed that CA and OTA jointly participate in key pathological processes such as the cancer pathway, the lipid and atherosclerosis pathway, the advanced glycation end-products–receptor for advanced glycation end-products (AGE-RAGE) signaling pathway, the phosphatidylinositol 3-kinase–protein kinase B (PI3K-Akt) signaling pathway, the TNF signaling pathway, and the interleukin-17 (IL-17) signaling pathway. OTA exacerbates inflammatory responses, impairs insulin signaling, promotes hepatic steatosis, and disrupts systemic metabolic homeostasis, ultimately contributing to T2DM-NAFLD comorbidity. Conversely, cinnamaldehyde counteracts these pathological processes through multiple mechanisms, including antioxidant and anti-inflammatory effects as well as regulation of glucose and lipid metabolism, thereby restoring metabolic homeostasis. Conclusions: This study has preliminarily identified the toxicological targets of OTA and the potential intervention targets of CA, offering new avenues for preventing and intervening in OTA-induced metabolic toxicity. Furthermore, it provides a theoretical basis for CA as a potential multi-target therapeutic agent and presents novel insights worthy of further investigation into the prevention of T2DM-NAFLD comorbidity. Full article

With a lifetime risk estimated to be 1 in 8 in industrialized countries, breast cancer is the most frequent type of cancer among women worldwide and the second leading cause of cancer deaths in women. More importantly, current evidence suggests that in women aged <45 years, breast cancer is unquestionably the leading cause of cancer-related deaths. Hormonal therapy has an established role in the treatment of breast cancer. Hormonal therapy aims at preventing the stimulation of mitogenic estrogen-dependent pathways. Hormonal therapy can be performed through blocking the production of estrogens or through blocking the action of estrogens upon tumor cells. The action of estrogens upon tumor cells can be blocked through selective estrogen receptor modulators (SERMs) or through selective estrogen receptor downregulators (SERDs). Estrogen receptor mutation (ESR1 mutation) is one of the common mechanisms by which breast cancer becomes resistant to additional therapies from SERMs or aromatase inhibitors. Fulvestrant, an injectable anti-estrogen, is the SERD commonly used. Fulvestrant has no agonistic activity and causes degradation of the estrogen receptor. This agent is more active in postmenopause than premenopause and is indicated in the treatment of advanced breast cancer in case of disease progression during or after tamoxifen. Oral SERDs are being rapidly developed to replace fulvestrant with the potential of higher efficacy and lower toxicities. Novel agents such as complete estrogen receptor antagonists (CERANs), proteolysis targeting chimeras (PROTACs), and selective estrogen receptor covalent antagonists (SERCAs) are also promising therapies. This manuscript focuses on recent advances in the development of drugs targeting the estrogen receptor. Full article

The genus Epimedium L. comprises a group of perennial herbs widely distributed across East Asia, with five representative species that include Epimedium grandiflorum C. Morren, Epimedium brevicornu Maxim., Epimedium sagittatum (Sieb. et Zucc.) Maxim., Epimedium koreanum Nakai. and Epimedium pubescens Maxim. For centuries, these species have been used in traditional Chinese medicine for their aphrodisiac, anti-osteoporotic and estrogen-like properties in the treatment of erectile dysfunction, osteoporosis, rheumatoid arthritis and menopausal symptoms. The aim of this review is to present an extensive and updated synthesis of the phytochemistry, biological activities and therapeutic properties of these five species by examining the relationship between the phytochemical composition and their pharmacological properties. Phytochemical analyses indicate that Epimedium spp. are defined by their significant content of prenylated flavonol glycosides, including icariin, icaritin, icariside, baohuoside and epimedin A-C. Recent studies have confirmed that these compounds are responsible for the genus’ therapeutic potential. They possess a variety of effects, ranging from aphrodisiac and antioxidant properties to anti-inflammatory and immunomodulatory activities, as well as neuroprotective, cardioprotective and anticancer benefits. Although preclinical findings are increasingly compelling, robust clinical evidence is still lacking for all five species. Taken together, the data summarized here position Epimedium spp. as a valuable source of bioactive prenylated flavonoids, while underscoring that standardized methodologies and rigorous clinical trials are essential to translate this potential into validated therapeutic applications. Full article

Improvement in the in vitro maturation (IVM) of oocyte quality is a gateway to enhancing the efficiency of in vitro embryo production. The anti-Müllerian hormone (AMH) is a crucial hormone secreted by granulosa cells that effectively suppresses primordial follicle recruitment and regulates follicular growth and development. This study was designed to investigate the role of AMH on the IVM of sheep oocytes. In this current study, oocytes in vitro were cultured in media supplemented with AMH. We comprehensively analyzed the impact of AMH on various developmental parameters of sheep oocytes, such as cellular activity, cortical granules (CGs) migration, cytoskeleton and mitochondrial function of oocytes. Furthermore, Smart-seq2 single-cell RNA sequencing (scRNA-seq) was employed to elucidate the oocytes’ development. The results showed that treatment with 100 ng/mL improved the maturation rate of the oocytes, the normal distribution rate of cortical granules and mitochondrial function, while reducing the rate of spindle abnormalities in oocytes. A total of 741 differentially expressed genes (DEGs) were observed between the FSH_12 h and AMH_12 h groups, and 746 DEGs were observed between the FSH_24 h and A+F groups. KEGG pathway analysis revealed that the FSH_12 h and AMH_12 h groups significant enrichment in DEGs were associated with p53, MAPK, PI3K-Akt and TGF-beta signaling pathways, and the FSH_12 h and AMH_24 h groups significant enrichment in DEGs were associated with cAMP, AMPK, Hedgehog and estrogen signaling pathways. These findings suggest that AMH may regulates oocytes IVM via several candidate signaling pathways. Our results provide preliminary clues for exploring the regulatory mechanism of sheep oocyte maturation and optimizing relevant culture systems. Full article

Dietary factors, including the consumption of isoflavones-rich foods of plant origin, may contribute to the reduced incidence of prostate cancer. Isoflavones, natural phytoestrogens often found in legumes, can modulate estrogen and androgen receptor signaling. This study aimed to evaluate the biological potential of isoflavone-rich extracts obtained from twelve species from the Fabaceae family, targeting prostate cancer cell viability, proliferation, inflammatory markers, prostate-specific antigen secretion, and 5α-reductase activity. The tested extracts showed moderate cytotoxic activity against prostate cancer cell lines, apart from highly susceptible PC3 cells, and only weak toxicity to normal prostate epithelial cells. Significant antiproliferative activity was observed, especially for Cytisus scoparius, Ononis arvensis, and Genista tinctoria, while most extracts reduced prostate-specific antigen (PSA) secretion in normal prostate cells. Furthermore, the extracts showed anti-inflammatory properties by reducing the pro-inflammatory cytokine interleukin 6 (IL-6) and improving cytokine balance indices. Multivariate analyses revealed correlations between total isoflavone content and antiproliferative activity. Full article

Allergic rhinitis (AR) is one of the most prevalent allergic disorders worldwide. Current pharmacological treatments are often limited by suboptimal efficacy and notable adverse effects. Herbal medicines, with their multi-component and multi-target therapeutic characteristics, have attracted increasing attention. Artemisia ordosica Krasch. (AOK), a traditional Chinese/Mongolian medicine has demonstrated immunomodulatory, antioxidant, and anti-inflammatory activities. The anti-AR potential of AOK extract fractions was evaluated using in vitro mast cell degranulation inhibition assays, network pharmacology analysis, molecular docking, and molecular dynamics simulations to elucidate underlying pharmacological mechanisms. The P815 mast cell model induced by compound 48/80 was employed to assess the inhibitory activity and cytotoxicity of different extract fractions. Among the tested fractions, the ethyl acetate fraction exhibited the most potent inhibitory effect on mast cell degranulation without significant cytotoxicity. Network pharmacology analysis identified 254 potential AR-related targets of AOK, with Signal Transducer and Activator of Transcription 3(STAT3), Src protein(SRC), Tumor protein 53(TP53), AKT Serine/Threonine Kinase 1(AKT1), Heat Shock Protein 90 Alpha Family Class A Member 1(HSP90AA1), Estrogen Receptor 1(ESR1), and Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha(PIK3CA) identified as key hub proteins. Gene Ontology and KEGG pathway enrichment analyses indicated that AOK primarily modulated inflammatory and oxidative stress-related processes through the lipid and atherosclerosis, hypoxia-inducible factor-1, and AGE-RAGE signaling pathways. Molecular docking and dynamics simulations demonstrated strong binding affinities and stable interactions between major active constituents, particularly hydroxygenkwanin, and key targets such as SRC. The ethyl acetate fraction of AOK extract exhibited significant mast cell degranulation inhibitory activity, likely mediated via a synergistic multi-component, multi-target mechanism involving regulation of inflammatory and immune-related signaling pathways. These findings provide a pharmacological basis for the potential application of AOK in AR treatment. Full article

Arctigenin (Arc), a novel anti-inflammatory lignan derived primarily from Arctium lappa, has demonstrated promising anticancer activity in multiple cancer types. This study was designed to evaluate the anticancer efficacy of Arc across distinct molecular subtypes of breast cancer in vitro and in vivo and to gain mechanistic insights into its mode of action. In vitro evaluation was conducted in estrogen-receptor-positive MCF-7, human epidermal growth factor receptor 2 (HER2)-positive SKBR3, and triple-negative MDA-MB-231 breast cancer cell lines. In vivo efficacy and safety were evaluated using female severe combined immunodeficient (SCID) mice (5–7 weeks old) bearing MCF-7 or MDA-MB-231 xenografts. Mice received daily oral gavage of Arc at 50 mg/kg body weight for 8 weeks. In vitro, Arc inhibited cell proliferation across all three breast cancer subtypes in a dose-dependent manner. PCR-array analysis of gene expression revealed that Arc targets multiple signaling molecules involved in cell proliferation, cell cycle regulation, apoptosis, migration/invasion, and drug transport, demonstrating a subtype-specific target profile. Arc induced cell-cycle arrest at the G2/M phase in MCF-7 cells and at G0/G1 in MDA-MB-231 cells, accompanied by significant induction of apoptosis in both cell lines. Migration assays further demonstrated marked inhibition of wound closure in Arc-treated cells. In vivo, Arc treatment significantly inhibited tumor growth in both xenograft models, decreased Ki67 expression, and produced no overt toxicity. In summary, Arc exhibits potent anticancer activity against distinct breast cancer subtypes through multi-targeting mechanisms. Given the heterogeneity of breast cancer, Arc appears to be a promising candidate for further preclinical investigation. Full article

Geroprotective molecules are currently being actively investigated for the prevention of skin aging. An overview of geroprotectors in dermatology encompasses agents such as antioxidants, ultraviolet (UV) photoprotective agents, chemical peels, and carbon dioxide (CO₂) lasers, each with inherent limitations, including poor tolerability in individuals with sensitive skin. Regarding biostimulators, high-molecular-weight peptides (exceeding 500 kDa) exhibit limited cutaneous bioavailability, underscoring the need for low-molecular-weight geroprotective compounds. One such candidate is dehydroepiandrosterone DHEA, a neurosteroid with anti-aging and anti-stress properties, which also serves as a precursor to sex steroids. Although topical hormone replacement therapy with estrogens and androgens is being utilized, it remains confined to formal hormone replacement regimens and is associated with a significant adverse effect profile. The aim of this review was to analyze the key molecular mechanisms underlying the effects of DHEA on the skin, with particular emphasis on its metabolism and sex- and age-dependent mechanisms of action. Additionally, this review seeks to elucidate the factors contributing to the absence of approved topical DHEA formulations and to outline the potential of DHEA as an anti-aging agent in dermatological applications. DHEA has demonstrated significant skin-improving effects in several studies; its investigation has been predominantly confined to postmenopausal women. Furthermore, the outcome measures employed in these studies lacked specificity. DHEA is not permitted for use in cosmetic products within the European Union due to its hormonal activity. Its use is only allowed as an extemporaneous formulation under the established regulatory frameworks of individual countries. The indications for its use and the appropriate dosage for men and women must be clearly defined based on the results of future clinical studies. Promising research directions include the pharmacogenetic characterization of steroidogenic enzymes and sex hormone receptors, as well as the evaluation of DHEA in both sexes, specifically in premenopausal women and in men presenting with late-onset hypogonadism. Additionally, the biological effects of the primary metabolites of DHEA, androstenedione, and 5-androstenediol, on the cutaneous function remain unexplored, including their potential anti-aging activity mediated through retinoid receptor activation. Full article

Ecdysterone is a natural compound proposed as an alternative to anabolic-androgenic steroids (AAS) due to its comparable ergogenic potential and more favorable safety profile. This narrative review summarizes current evidence using a standardized search protocol. Although many plants synthesize ecdysteroids, only a few cultivated species—emphasizing quinoa and spinach—contribute meaningfully to dietary intake, while wild species such as those from the Ajuga genus contain substantially higher concentrations. Experimental studies indicate that ecdysterone enhances protein synthesis and physical performance through estrogen receptor-beta activation, avoiding the adverse effects typically associated with AAS. Additional pharmacological effects, including potential roles in breast cancer therapy and Alzheimer’s disease, have also been described. Ecdysteroids are generally considered non-toxic in humans; however, analysis of commercial supplements frequently reveals poor quality control and discrepancies between labeled and actual ecdysterone content. Although prevalence of use among athletes appears low, establishing urinary reference ranges to differentiate dietary exposure from supplement-derived intake is essential. Ecdysterone and its metabolites, 14-deoxy-ecdisterone and 14-deoxy-poststerone, are detectable in urine for more than two days depending on dosage. Given its ergogenic potential and detectability, ecdysterone may pose risks for unethical use and should be considered for inclusion in initial anti-doping testing procedures. Further research on ecdysteroids is required to elucidate their mechanisms of action, confirm the absence of adverse effects, and establish reference urinary concentration ranges that allow differentiation between diet-related metabolites and those derived from drug use. Full article

Androgen receptor (AR) signaling has emerged as a potential molecular target in triple-negative breast cancer (TNBC), a clinically aggressive and biologically heterogeneous subtype of breast cancer with limited targeted treatment options. Androgens, the main ligands of AR, have been reported to exert antiproliferative and anti-estrogenic effects in normal mammary epithelium; however, the role of AR signaling in TNBC remains controversial and appears to depend strongly on tumor molecular context. In certain experimental settings, elevated androgen levels have been associated with reduced tumor growth, whereas AR activation has also been linked to signaling pathways involved in cell survival, migration, and invasiveness. AR signaling can occur through classical androgen-dependent mechanisms, as well as through ligand-independent activation mediated by protein kinases and intracellular pathways. Increasing interest in AR biology has led to the evaluation of several anti-androgen therapies in AR-positive TNBC, including agents such as enzalutamide, enobosarm, orteronel, bicalutamide, and seviteronel. Although clinical activity has generally been modest, these studies highlight the potential relevance of AR-targeted strategies in selected patient subgroups. This review summarizes current knowledge on androgen and AR signaling in TNBC, integrating molecular mechanisms, preclinical evidence, and clinical studies, and discusses emerging therapeutic strategies aimed at improving patient treatment outcomes. Full article

Background: Tectoridin is a prominent isoflavone glycoside found in herbs such as Belamcanda chinensis (L.) DC and Iris tectorum Maxim. It has drawn increasing research interest due to its promising pharmacological activities. However, no critical review to date has determined whether its broad pharmacological activity stems from binding to specific targets or from the non-specific, broad-spectrum activity commonly associated with flavonoids. This paper provides a comprehensive review of tectoridin, covering its plant sources, pharmacological effects, pharmacokinetics, and toxicity, alongside an in-depth analysis of the mechanisms underlying its pharmacological effects and strategic recommendations for advancing its clinical translation. Methods: A systematic literature search was conducted in PubMed, Web of Science, Google Scholar, SciFinder, and CNKI for publications from 1968 to 2025 using keywords including tectoridin, tectorigenin 7-O-glucoside, traditional uses, ethnopharmacology, pharmacology, bioactive compounds, biological activity, pharmacokinetics and toxicity. Results: Tectoridin exhibits a broad spectrum of pharmacological activities, including anticancer, anti-inflammatory, hepatoprotective, antidiabetic, antioxidant, cardiovascular, and estrogenic effects. Pharmacokinetic studies have shown rapid tissue distribution and slow elimination; the aglycone metabolite tectorigenin often displays enhanced bioactivity, and chemical modifications may further improve efficacy. Toxicity data suggest relative safety in medicinal food contexts, but comprehensive in vivo studies remain limited. Tectoridin shows promise for treating cancer and inflammatory diseases; however, further research is needed to elucidate its molecular mechanisms, clarify toxicity, and optimize bioactivity. Conclusions: This review bridges natural products and modern therapeutics by focusing on tectoridin, highlighting its therapeutic potential, addressing challenges, and offering new perspectives for treating various diseases. Full article

Cardiac fibrosis is a central determinant of heart failure progression and arises from pathological remodeling characterized by fibroblast activation, myofibroblast differentiation, and excessive extracellular matrix deposition. In contrast, physiological remodeling permits adaptive cardiac growth without net fibrosis. Pregnancy represents an underexplored physiological model of reversible cardiac remodeling. In response to hemodynamic load, the maternal heart undergoes hypertrophic growth that resolves postpartum, constituting a natural paradigm of fibrosis-resistant cardiac adaptation. Pregnancy and lactation are accompanied by profound endocrine and immune reprogramming of maternal tissues. We propose that this hormonal milieu orchestrates coordinated crosstalk among endothelial cells, fibroblasts, and immune cell populations to suppress profibrotic pathways and preserve extracellular matrix homeostasis. Candidate regulators include estrogen, progesterone, prolactin family peptides, relaxin, oxytocin, and components of the renin–angiotensin–aldosterone system. During the postpartum and lactational period, prolactin and oxytocin may further promote reverse remodeling. These hormones likely act by modulating local cytokine and growth factor networks that otherwise drive fibroblast activation. By focusing on non-myocyte cardiac cells and extracellular matrix dynamics, this review positions pregnancy as a translational model to uncover endogenous anti-fibrotic mechanisms and identify novel therapeutic strategies for cardiac fibrosis. Full article