Search Results (116)

Background and Objectives: PAPSS2 loss-of-function variants cause autosomal recessive brachyolmia type 4 with skeletal dysplasia. Despite over 90 documented cases, molecular characterization remains incomplete, with many variants classified as uncertain significance (VUS). Materials and Methods: We performed integrated multi-modal in silico analysis of two novel and rare homozygous missense variants [c.227T>A p.(Leu76Gln) and c.143C>G p.(Thr48Arg)] identified via whole-exome sequencing in two unrelated Turkish girls. Analysis incorporated AlphaMissense (0.92, 0.96), REVEL (0.85), CADD Phred (28.8–29.1), evolutionary conservation across seven vertebrate species (100% identity), and AlphaFold2 structural modeling. Variant reclassification followed 2015 ACMG/AMP guidelines. Results: Both variants fulfilled criteria for VUS-to-Likely Pathogenic reclassification: PS3 (functional loss), PM1 (critical APS-kinase domain localization), PM2 (population rarity), and PP3 (computational consensus). Structurally, p.(Leu76Gln) disrupts hydrophobic core stability (Grantham score 113), while p.(Thr48Arg) causes active-site steric hindrance. Both probands presented with platyspondyly, short stature, and profound DHEA-sulfate depletion (3.15 and 1.79 µg/dL). Although identical variants were reported in a 14.5-year-old with PCOS-like androgen excess, our prepubertal cases (ages 5–6 years) exhibited normal androgens, suggesting PAPSS2 loss-of-function is necessary but insufficient for androgen excess. Conclusions: Multi-modal computational analysis supports likely pathogenic reclassification of these PAPSS2 variants, enabling precision genetic counseling and advancing understanding of skeletal and endocrine heterogeneity. These findings expand the PAPSS2 variant registry to over 92 cases across 18 countries. Full article

Background: High-risk (HR) prostate cancer has a propensity for local and distant progression with ultimate death, mandating aggressive locoregional and systemic treatment approaches to maximize oncologic outcomes. Although brachytherapy (BT) with supplemental therapies has demonstrated favorable biochemical and quality of life outcomes, improvements in overall survival have been hampered by an excessive incidence of non- prostate cancer deaths. In this HR study, we report on biochemical failure (BF), prostate cancer-specific mortality (PCSM), overall mortality (OM) and patterns of death with recommendations for the mitigation of non-prostate cancer deaths. Materials and Methods: From April 1995 to November 2018, 577 consecutive HR patients were treated with LDR BT (97.9% Pd-103). Patients were stratified into three age cohorts: ≤ 59, 60–69 and ≥70 years. The BT prescription dose was prescribed to the prostate gland with generous peri-prostatic margins and the proximal 10mm of the seminal vesicles. 94.6% received supplemental EBRT (45–50.4 Gy) and 63.3% received androgen deprivation therapy (ADT) (median duration 12 months). Post-implant CT-based dosimetry was performed on day 0. BF was defined as a PSA > 0.40 ng/mL after nadir. The cause of death was determined for each patient. Patients with metastatic prostate cancer or non-metastatic castrate resistant prostate cancer who died of any cause were classified as dead of prostate cancer. All other deaths were attributed to the immediate cause. Multiple clinical, pathologic and treatment were evaluated for impact on patient outcomes. Results: Of the patients, 87.5% (median follow-up 8.9 years) presented with a single HR factor. The day 0 D90 was 122.5%. Overall, the 15-year BF, PCSM and OM were 12.4%, 5.6% and 51.7%. When stratified by age, there was no significant difference in BF or PCSM. The median post- treatment PSA in biochemically controlled patients was <0.01 ng/mL. In all three cohorts, OM increased linearly for the first 10 years and then approximately doubled from years 10 to 15. Moreover, 239 patients died: 10.9% due to prostate cancer, 38.1% from cardiovascular (CV) disease and 28.4% from other malignancies (to include one rectal and three bladder cancers). In MVA, BF was most closely related to percent positive biopsies (p < 0.001, SHR 1.018), PCSM to Gleason score (p = 0.004, SHR 2.884) and percent positive biopsies (p = 0.005, SHR 1.021) and OM to age (p < 0.001, HR 1.075) and tobacco (p < 0.001, HR 2.374). Conclusions: Despite high cancer control rates, overall survival was limited by a preponderance of CV and non-prostate cancer deaths, which were 6 times more likely than prostate cancer deaths. The implementation of a comprehensive multidisciplinary survivorship program will be essential to impact longevity in this patient population. Full article

Polycystic ovary syndrome (PCOS) is frequently accompanied by visceral obesity, insulin resistance, low-grade chronic inflammation, and metabolic syndrome (MetS). These alterations promote significant dysfunction in adipose tissue and liver metabolism through cytokine production. Growing evidence indicates that the interaction between hepatokines and adipokines plays a central role in the development of metabolic and hepatic abnormalities in women with PCOS. This narrative review was conducted to analyze the relationship between adipose tissue dysfunction and liver metabolic impairment in women with PCOS, emphasizing the involvement of hepatokines and adipokines in insulin resistance, inflammation, hepatic steatosis, hepatic fibrosis and MetS. From this perspective, contemporary clinical, biochemical, and molecular studies were reviewed to evaluate how adipocyte-derived factors and hepatocyte-derived cytokines influence metabolic homeostasis in the liver and adipose tissue in women with PCOS. Increased visceral adiposity in PCOS enhances the release of free fatty acids (FFAs) to the liver, resulting in hepatotoxicity, oxidative stress, and hepatic inflammation. Several hepatokines, including fetuin-A, angiopoietin-like protein 3 (ANGPTL3), selenoprotein P(Sep-P), and hepassocin (HPS), show abnormal circulating levels in PCOS and are strongly associated with insulin resistance, dyslipidemia, and progression to hepatic steatosis. In contrast, fibroblast growth factor 21 (FGF-21), follistatin, and interleukin (IL-6) may exert dual effects. Adipokines, such as resistin, visfatin, apelin, and retinol-binding protein 4 (RBP-4), contribute to chronic inflammation, impaired glucose metabolism, androgen excess, and hepatic steatosis and fibrosis. Some of these adipokines, such as leptin and vaspin, may exert both beneficial and detrimental effects, while others, including chemerin and omentin, appear to play predominantly beneficial roles in metabolism. Reduced adiponectin-to-leptin levels further aggravate metabolic dysfunction. These changes indicate that adipose tissue–liver crosstalk is a key mechanism linking PCOS and MetS. Overall, metabolic disturbances in PCOS are strongly mediated by dysregulated communication between adipose tissue and the liver. Altered hepatokine and adipokine profiles contribute to insulin resistance, liver dysfunction, hypertension and the development of MetS in women with PCOS. Understanding these intricate interactions may support the early identification of high-risk patients and the development of targeted therapeutic strategies. Full article

Polycystic ovarian syndrome (PCOS) affects over 116 million women globally and is typically linked with excess androgens such as testosterone. Many patients, however, display classic PCOS symptoms despite normal serum androgen. One proposed mechanism for these cases involves a shortened CAG (i.e., encodes glutamine) repeat length in the androgen receptor (AR) gene, which increases AR activity without elevating testosterone. Fewer glutamine repeats alter the AR’s N-terminal domain and may contribute to strengthened interactions with co-activators and enhanced transcription of androgen-regulated genes. Heightened AR activity in hypothalamus neurons stimulates increased pulsatile release of gonadotropin-releasing hormone (GnRH), which disrupts pituitary secretion dynamics and favors luteinizing hormone (LH) over follicle-stimulating hormone (FSH). This altered LH/FSH ratio leads to impaired folliculogenesis, anovulation and other hallmark PCOS symptoms. Targeting AR activity directly, for example by using compounds that covalently modify the AR N-terminal domain to suppress activity, may therefore offer a more precise treatment strategy for PCOS. Full article

Alopecia is a multifactorial disorder in which immune, endocrine, metabolic, and microbial systems converge within the follicular microenvironment. In alopecia areata (AA), loss of immune privilege, together with interferon-γ- and interleukin-15-driven activation of the JAK/STAT cascade, promotes cytotoxic infiltration, whereas selective inhibitors, including baricitinib, ritlecitinib, and durvalumab, restore immune balance and permit anagen reentry. In androgenetic alopecia (AGA), excess dihydrotestosterone and androgen receptor signaling increase DKK1 and prostaglandin D2, suppress Wnt and β-catenin activity, and drive follicular miniaturization. Combination approaches utilizing low-dose oral minoxidil, platelet-rich plasma, exosome formulations, and low-level light therapy enhance vascularization, improve mitochondrial function, and reactivate metabolism, collectively supporting sustained regrowth. Elucidation of intracellular axes such as JAK/STAT, Wnt/BMP, AMPK/mTOR, and mitochondrial redox regulation provides a mechanistic basis for rational, multimodal intervention. Advances in stem cell organoids, biomaterial scaffolds, and exosome-based therapeutics extend treatment from suppression toward structural follicle reconstruction. Recognition of microbiome and mitochondria crosstalk underscores the need to maintain microbial homeostasis and redox stability for durable regeneration. This review synthesizes molecular and preclinical advances in AA and AGA, outlining intersecting signaling networks and regenerative interfaces that define a framework for precision and sustained follicular regeneration. Full article

Polycystic ovary syndrome (PCOS) is a complex disorder characterized by reproductive abnormalities such as hyperandrogenism, ovulatory dysfunction, and polycystic ovarian morphology, and is frequently accompanied by metabolic disturbances such as insulin resistance, obesity and dyslipidemia. Genome-wide association studies (GWASs) have identified several susceptibility loci, yet little is known about their functional implications. Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (CRISPR/Cas9) has emerged as a powerful gene editing tool in bridging this gap by allowing researchers to directly target candidate genes in ovarian and metabolic pathways. For instance, experimental models have highlighted the role of CYP17A1 and DENND1A.V2 in androgen excess, anti-Müllerian hormone (AMH) in follicular arrest, and insulin receptor substrate 1 (IRS1) and PPARγ in insulin signaling and adipogenesis. To highlight the multifactorial nature of PCOS, animal models, including zebrafish and rodents, have been used to reveal interactions between reproductive and metabolic phenotypes. Nevertheless, most studies remain restricted to single-gene models, and dual-gene models or combined gene editing and hormonal induction models remain underexplored. Future research integrating precision editing, multi-omic platforms, and patient-derived organoids may provide more accurate disease models and novel therapeutic strategies. Full article

Polycystic ovary syndrome (PCOS) represents one of the most prevalent endocrine–metabolic disorder in women of reproductive age, which includes but not restricted to reproductive disruptions, insulin resistance (IR), hyperandrogenism, and chronic low-grade inflammation. Its heterogeneous pathophysiology arises from the interplay of metabolic, endocrine, and immune factors, including dysregulated adipokine secretion, cytokine-mediated inflammation, oxidative stress (OS), and mitochondrial dysfunction. Current pharmacological therapies, such as metformin, clomiphene, and oral contraceptives, often provide partial benefits and are limited by side effects, necessitating the exploration of safer, multi-target strategies. Flavonoids, a structurally diverse class of plant-derived polyphenols, have gained attention as promising therapeutic candidates in PCOS due to their antioxidant, anti-inflammatory, insulin-sensitizing, and hormone-modulating properties. Preclinical studies in rodent PCOS models consistently demonstrate improvements in insulin sensitivity, normalization of ovarian morphology, restoration of ovulation, and reduction in hyperandrogenism. Human clinical studies, though limited in scale and heterogeneity, report favorable effects of flavonoids such as quercetin, isoflavones, and catechins on glucose metabolism, adipokine balance, inflammatory markers, and reproductive functions. This evidence-based study critically synthesizes mechanistic insights into how flavonoids modulate insulin signaling, adipokine–cytokine crosstalk, OS, and androgen excess, while highlighting translational evidence and emerging delivery systems aimed at overcoming bioavailability barriers. Collectively, flavonoids represent a promising class of nutraceuticals and adjuncts to conventional therapies, offering an integrative strategy for the management of PCOS. Full article

Muscle dysmorphia (MD) is a body image disorder characterized by an obsessive preoccupation with muscularity and compulsive behaviors such as excessive exercise, rigid dieting, and frequent body checking. MD has been linked to obsessive–compulsive traits and the use of anabolic–androgenic steroids (AASs), yet these associations have not been comprehensively synthesized. This systematic review and meta-analysis examined the relationships between MD, obsessive–compulsive symptomatology, and AASs or performance-enhancing drug use. Following PRISMA 2020 guidelines and PROSPERO preregistration (CRD42025640206), we searched four major databases for peer-reviewed studies published between 2015 and 2025. Ten studies (five quantitative, five qualitative) met the inclusion criteria. Meta-analytic findings revealed a moderate positive correlation between MD symptom severity and obsessive–compulsive traits (r ≈ 0.24), and significantly higher MD symptoms among AAS users compared to non-users (Cohen’s d ≈ 0.45). Odds of MD were markedly higher in steroid-using populations. Thematic synthesis of qualitative studies highlighted compulsive training routines, identity conflicts, motivations for AAS use, and limited engagement with healthcare services. These findings suggest that MD exists at the intersection of obsessive–compulsive psychopathology and substance-related behavior, warranting integrated interventions targeting both dimensions. The study contributes to understanding MD as a complex, multi-faceted disorder with significant clinical and public health relevance. Full article

(1) Polycystic ovary syndrome (PCOS) is one of the most common endocrinological disorders worldwide; its complex etiopathology remains poorly understood. PCOS is associated with a broad spectrum of abnormalities, including irregular menses, androgen excess, and increased risk of metabolic, endocrinological, and cardiovascular disorders. This narrative review focuses on structural and functional changes in the uterus associated with polycystic ovary syndrome and hyperandrogenism. (2) The review was performed by searching PubMed, Medline, Embase, Google Scholar, and Cochrane Library electronic databases on records published between 1964 and 2025. The authors included studies on (i) the uterus in clinical settings of PCOS patients, (ii) the uterus in PCOS models, and (iii) the pregnant uterus in patients with PCOS. Multiple animal and human studies describe a potential impact of PCOS on uterine blood flow, morphology, and thickness of the uterine muscle, indicating a possible functional impairment in pregnant and non-pregnant women. The scope of available knowledge regarding functional and structural uterine changes in PCOS is scarce; new studies are warranted. Future research should focus on hyperandrogenism associated with PCOS and explore the link between the morphology and function of the uterus. Full article

Background: Idiopathic Hyperandrogenism (IH) is often encountered in the general population and particularly in women presenting with androgen excess. It is diagnosed in women who have normal ovulatory cycles, elevated androgen levels, and normal appearing ovaries on ultrasound. Using serum anti-mullerian hormone (AMH), which has been suggested to be a surrogate marker of polycystic ovarian morphology, we wished to determine if some women with IH may have the ovulatory phenotype of PCOS, where metabolic abnormalities may be more prevalent. Methods: This was a retrospective study of 84 women diagnosed with IH and 50 age- and BMI-matched ovulatory controls who were evaluated between 2021 and 2024. Androgen levels, ovarian ultrasound, and serum AMH were assessed. In addition, glucose, insulin, HOMA-IR, and lipid levels were measured. Results: Twenty-four women (29%) with IH had elevated AMH levels (>4.7 ng/mL). None of the control women had elevated values. These 24 women with IH had values ranging from 5.5–11.9 ng/mL, compared to the other 60 women whose AMH levels were 0.8–4.3 ng/mL. Age and weight were similar in these two subgroups of women with IH. Glucose, insulin, and HOMA-IR were similar in the two groups, but cholesterol and LDL-cholesterol were elevated in the 24 women with elevated AMH. Elevations in LDL-cholesterol were observed in 3.5% of the women with normal AMH and in 21% of those with elevated AMH. Conclusions: Despite normal ovarian morphology on ultrasound, approximately 30% of women with IH were found to have elevated AMH and may be considered to have the ovulatory phenotype of PCOS. These women also have some metabolic dysfunction, which is more characteristic of women with PCOS. These data reinforce the notion that AMH findings are not always concordant with ovarian morphological findings and suggest wider implication of elevated AMH levels in the pathophysiology of PCOS. Full article

Background: Polycystic Ovary Syndrome (PCOS) is a prevalent endocrine disorder characterized by excess body weight, hyperandrogenism, hyperglycemia, and insulin resistance often resulting in hirsutism and infertility. Dietary strategies have been shown to ameliorate metabolic disturbances, hormonal imbalances, and inflammation associated with PCOS. Recent evidence indicates that intermittent fasting (IF) could effectively enhance health outcomes and regulate circadian rhythm; however, its impact on PCOS remain unclear. Objective: Therefore, this systematic review and meta-analysis aims to examine the effect of IF on women diagnosed with PCOS. Methods: Comprehensive research was conducted across three major databases including PubMed, Scopus, and Web of Science without date restrictions. Meta-analysis was performed using Cochrane Review Manager Version 5.4 software. Results: Five studies fulfilled the inclusion criteria. IF significantly reduced body weight (MD = −4.25 kg, 95% CI: −7.71, −0.79; p = 0.02), BMI (MD = −2.05 kg/m², 95% CI: −3.26, −0.85; p = 0.0008), fasting blood glucose (FBG; MD = −2.86 mg/dL, 95% CI: −4.83, −0.89; p = 0.004), fasting blood insulin (FBI; MD = −3.17 μU/mL, 95% CI: −5.18, −1.16; p = 0.002), insulin resistance (HOMA-IR; MD = −0.94, 95% CI: −1.39, −0.50; p < 0.0001), triglycerides (TG; MD = −40.71 mg/dL, 95% CI: −61.53, −19.90; p = 0.0001), dehydroepiandrosterone sulfate (DHEA-S; MD = −33.21 μg/dL, 95% CI: −57.29, −9.13; p = 0.007), free androgen index (FAI; MD = −1.61%, 95% CI: −2.76, −0.45; p = 0.006), and C-reactive protein (CRP; MD = −2.00 mg/L, 95% CI: −3.15, −0.85; p = 0.006), while increasing sex hormone-binding globulin (SHBG; SMD = 0.50, 95% CI: 0.22, 0.77; p = 0.004). No significant changes were observed in waist-to-hip ratio (WHR), total cholesterol (TC), LDL, HDL, total testosterone (TT), or anti-Mullerian hormone (AMH). Conclusions: IF represents a promising strategy for improving weight and metabolic, hormonal, and inflammatory profiles in women with PCOS. However, the existing evidence remains preliminary, necessitating further robust studies to substantiate these findings. Full article

Background/Objectives: Ovarian follicular cysts (OFCs) in dairy cows represent a significant cause of infertility and share striking similarities with polycystic ovary syndrome (PCOS) in women. This study aimed to elucidate the molecular mechanisms underlying OFCs and their relevance to PCOS by profiling differentially expressed (DE) microRNAs (miRNAs) and constructing integrative RNA interaction networks. Methods: Expression analysis of 84 bovine miRNAs was conducted in antral follicular fluid from normal and cystic follicles using miScript PCR arrays. Bioinformatic tools including miRBase, miRNet, and STRING were employed to predict miRNA targets, construct protein–protein interaction networks, and perform gene ontology and KEGG pathway enrichment. Network analyses integrated miRNAs with coding (mRNAs) and non-coding RNAs (circRNAs, lncRNAs, snRNAs). Results: Seventeen miRNAs were significantly dysregulated in OFCs, including bta-miR-18a, bta-miR-30e-5p, and bta-miR-15b-5p, which were associated with follicular arrest, insulin resistance, and impaired steroidogenesis. Upregulated miRNAs such as bta-miR-132 and bta-miR-145 correlated with inflammation, oxidative stress, and intrafollicular androgen excess. Key regulatory lncRNAs such as Nuclear Enriched Abundant Transcript 1 (NEAT1), Potassium Voltage-Gated Channel Subfamily Q Member 1 Opposite Strand/Antisense Transcript 1 (KCNQ1OT1), Taurine-Upregulated 1 (TUG1), and X Inactive Specific Transcript (XIST), as well as circRNA/pseudogene hubs, were identified, targeting pathways involved in metabolism, inflammation, steroidogenesis, cell cycle, and apoptosis. Conclusions: The observed transcriptomic changes mirror core features of human PCOS, supporting the use of bovine OFCs as a comparative model. These findings provide novel insights into the regulatory RNA networks driving ovarian dysfunction and suggest potential biomarkers and therapeutic targets for reproductive disorders. This network-based approach enhances our understanding of the complex transcriptomic landscape associated with follicular pathologies in both cattle and women. Full article

Background/Objectives: Polycystic ovary syndrome (PCOS) is one of the most frequently diagnosed endocrine and metabolic disorders in women of reproductive age before menopause. It is associated with excess androgens and ovarian dysfunction, reduced fertility, the presence of obstetric disorders, but also metabolic disorders, and, among others, insulin resistance, obesity and type II diabetes. Its close relationship with changes in the diversity of the vaginal microbiome, vaginal inflammation and changes in the vaginal microenvironment, which can pave the way for pathogenic microorganisms, is emphasized. Methods: The research in the presented paper focuses on a group of women with PCOS (n = 490) of reproductive age (26–43 years), in whom the frequency of infections of the reproductive system caused by atypical pathogens, Chlamydia trachomatis, Mycoplasma hominis and Ureaplasma spp., were analyzed, and then the immune system response was assessed in terms of the level of serum proinflammatory cytokines, IL-1β, IL-6 and TNF-α. Results: Our results showed a 40% infection rate in the studied group of patients with PCOS, with C. trachomatis being the most common pathogen (17.7%), followed by Ureaplasma spp. (10%) and M. hominis (4.9%). In some cases, co-infections such as Mycoplasma and Ureaplasma were also observed in 3.1% or all three atypical bacteria, M. hominis, Ureaplasma spp. and C. trachomatis, in 4.3% of patients with PCOS. In our study, in women with PCOS and confirmed infection with any atypical pathogen (n = 196), we analyzed the levels of proinflammatory cytokines, IL-1 β a, IL-6 and TNF-α. The results were compared with a control group (control group A) consisting of patients with the same underlying disease, i.e., PCOS (n = 39), who did not experience infection with atypical pathogens or symptoms of gynecological infection. Additionally, a control group B (n = 28) consisting of healthy women (without PCOS and without infection) was introduced. The results regarding the levels of cytokines studied in this work (IL-1β, IL-6, TNF-α) may suggest that the presence of intracellular C. trachomatis in the infection will play a dominant role in the immune system response. In the infections with atypical pathogens analyzed in this study in patients with PCOS, no characteristic clinical features were observed, apart from indications in the form of an increase in the number of leukocytes in the assessment of the vaginal biocenosis, suggesting cervicitis and reported reproductive failure or lower abdominal pain. An additional problem is the inability to detect the presence of atypical pathogens in routine microbiological tests; therefore, confirmation of such etiology requires referral of the patient for targeted tests. Conclusions: Invasion of host cells by atypical pathogens such as C. trachomatis and infections with “genital mycoplasmas” can disrupt the function of these cells and lead to many complications, including infertility. The immune response with the production of proinflammatory cytokines such as TNF-α, IL-1β, and IL-6, observed in response to infection with C. trachomatis, M. hominis, and Ureaplasma spp., induces or amplifies inflammation by activating immune cells or controlling infection, but may lead to the facilitation of the survival of pathogenic microorganisms and irreversible damage to fallopian tube tissues. Especially in the case of the proinflammatory cytosine TNF-α, there seems to be a close correlation with infections with atypical pathogens and a marked immune response, as well as with increased IL-1β and IL-6 values compared with the absence of infection (both in the presence and absence of PCOS). The presented study may suggest the importance of extended diagnostics to include atypical pathogens in the case of PCOS and the importance of research in this area also from the point of view of the immune response. Full article

Hirsutism, characterized by excessive terminal hair growth in androgen-sensitive areas, presents significant medical and psychosocial challenges in Gulf Cooperation Council (GCC) countries. This narrative review explores the epidemiology, endocrine factors, molecular basis of pathophysiology, cultural influences, and management approaches to hirsutism within the GCC. Regional factors such as consanguinity, rising obesity rates, and lifestyle habits contribute to a higher prevalence of hirsutism and related endocrine disorders, particularly polycystic ovary syndrome (PCOS). Cultural stigmas surrounding body hair further delay diagnosis and treatment, compounding psychological distress. The review examines the role of androgen excess, genetic susceptibility, and emerging molecular insights, including epigenetic dysregulations. Diagnostic limitations and the need for region-specific screening tools are discussed, alongside the current reliance on pharmacological, cosmetic, and traditional therapies. Public health initiatives targeting stigma reduction and early detection are emphasized. Future recommendations include culturally tailored research, enhanced public awareness, and the adoption of advanced diagnostic strategies to improve patient outcomes. This review aims to guide healthcare practices and inform policy development for the better management of hirsutism in the GCC context. Full article

Heart failure represents the terminal stage in the development of many cardiovascular diseases, and its pathological mechanisms are closely related to disturbances in energy metabolism and mitochondrial dysfunction in cardiomyocytes. In recent years, nicotinamide adenine dinucleotide (NAD⁺), a core coenzyme involved in cellular energy metabolism and redox homeostasis, has been shown to potentially ameliorate heart failure through the regulation of mitochondrial function. This review systematically investigates four core mechanisms of mitochondrial dysfunction in heart failure: imbalance of mitochondrial dynamics, excessive accumulation of reactive oxygen species (ROS) leading to oxidative stress injury, dysfunction of mitochondrial autophagy, and disturbance of Ca²⁺ homeostasis. These abnormalities collectively exacerbate the progression of heart failure by disrupting ATP production and inducing apoptosis and myocardial fibrosis. NAD⁺ has been shown to regulate mitochondrial biosynthesis and antioxidant defences through the activation of the deacetylase family (e.g., silent information regulator 2 homolog 1 (SIRT1) and SIRT3) and to increase mitochondrial autophagy to remove damaged mitochondria, thus restoring energy metabolism and redox balance in cardiomyocytes. In addition, the inhibition of NAD⁺-degrading enzymes (e.g., poly ADP-ribose polymerase (PARP), cluster of differentiation 38 (CD38), and selective androgen receptor modulators (SARMs)) increases the tissue intracellular NAD⁺ content, and supplementation with NAD⁺ precursors (e.g., β-nicotinamide mononucleotide (NMN), nicotinamide riboside, etc.) also significantly elevates myocardial NAD⁺ levels to ameliorate heart failure. This study provides a theoretical basis for understanding the central role of NAD⁺ in mitochondrial homeostasis and for the development of targeted therapies for heart failure. Full article