Search Results (4,295)

Sphingosine-1-phosphate (S1P) signaling has emerged as a regulator of metabolic homeostasis, but its relationship to brown adipose tissue (BAT) adaptation across physiological conditions remains unclear. We examined how S1P-related gene expression in BAT and subcutaneous white adipose tissue (scWAT) varies with acute exercise, chronic exercise, ambient temperature, aging, sex, and UCP1 deficiency. Young and aged wild-type mice, as well as aged UCP1 knockout (UCP1KO) mice, were studied across acute or chronic exercise paradigms and thermal conditions ranging from 4 °C to 30 °C. In BAT, acute exercise was associated with lower S1pr1, S1pr2, and Sphk1 expression in young females, whereas aged males showed lower S1pr2 and Sphk1 after exercise. In scWAT, exercise-associated induction of S1P-related transcripts was most evident in aged males. Female BAT also displayed broader temperature- and chronic exercise-associated differences in S1pr2, Sphk1, and β-adrenergic receptor transcripts, whereas male BAT showed fewer transcriptional changes. In UCP1KO mice, these exercise-associated patterns were altered or attenuated. Together, these findings identify a context-dependent adipose S1P-related transcriptional program that differs by sex, age, depot, ambient temperature, exercise condition, and UCP1 status. Full article

Triple-negative breast cancer (TNBC) lacking androgen receptor (AR) expression defines quadruple-negative breast cancer (QNBC), which is characterized by younger age at diagnosis, high Ki-67 index, and high genomic instability, however a comprehensive description of the genomic characteristics remains poorly defined. A total of 54 TNBC cases were categorized as TNBC with 100% AR expression (TNBC AR-100%) or QNBC, TNBC with 0% AR expression (TNBC AR-0%). Clinical, molecular, and genomic parameters, specifically pathogenic/likely pathogenic (P/LP) variants in homologous recombination repair (HRR) and cancer-related pathways were measured and analyzed. The QNBC cohort exhibited a high homologous recombination deficiency (HRD) score and a greater overall incidence of copy number variants (CNVs). QNBC harbored a higher mutation rate in TP53 and MYC signaling pathway than TNBC AR-100% tumors. P/LP variants corresponding to the HRR, PI3K/AKT, and RTK/RAS pathways were exclusively identified in QNBC. These results suggest that, at both molecular and genomic levels, the two groups are distinct, holding QNBC tumors more aggressive characteristics, genomic instability, and particular impairments in HRR and cancer-related pathways. In terms of actionability, these differences could potentially be leveraged through different combinations of therapies. Full article

Obesity is a multifactorial condition that profoundly affects female reproductive health through endocrine, metabolic, and inflammatory mechanisms that disrupt the hypothalamic–pituitary–gonadal (HPG) axis. Women with obesity frequently develop menstrual irregularities, anovulation, amenorrhea, infertility, polycystic ovary syndrome (PCOS), impaired endometrial receptivity, and adverse pregnancy outcomes. Central obesity and insulin resistance contribute to hyperinsulinemia, reduced sex hormone-binding globulin (SHBG) levels, hyperandrogenism, altered gonadotropin secretion, and impaired folliculogenesis, while adipokines such as leptin and chronic inflammation further impair ovarian steroidogenesis and ovulatory function. Obesity-related oxidative stress and lipotoxicity also negatively affect oocyte quality, embryo development, implantation, and assisted reproductive technology outcomes, increasing the risk of gestational diabetes, preeclampsia, miscarriage, and preterm birth. This review evaluates the therapeutic potential of pharmacological weight-loss therapies in obesity-associated female reproductive dysfunction. A comprehensive literature review was conducted using various databases, focusing on anti-obesity pharmacotherapy on obesity, infertility and fertility in reproductive-aged women. Evidence suggests that several FDA-approved and off-label anti-obesity agents, including orlistat, liraglutide, semaglutide, phentermine/topiramate, bupropion/naltrexone, metformin, exenatide, and tirzepatide, may improve reproductive outcomes primarily indirectly through weight reduction and metabolic improvement. GLP-1 receptor agonists, particularly liraglutide, semaglutide, and exenatide, appear especially promising, demonstrating beneficial effects on insulin sensitivity, menstrual regularity, ovulation, androgen levels, and pregnancy rates in women with PCOS. Tirzepatide, a dual GLP-1/GIP receptor agonist, has shown potent weight-loss and metabolic effects with potential indirect fertility benefits. Metformin improves insulin sensitivity and is widely used in PCOS to regulate androgen levels and restore ovulation, although its effects on pregnancy and live birth rates remain controversial. However, evidence for several agents remains limited, and concerns persist regarding reproductive safety during pregnancy. Overall, anti-obesity pharmacotherapy may represent an important adjunctive strategy for improving reproductive and metabolic health in women with obesity, although larger randomized clinical trials are still required. Full article

Background/Objectives: Individualized treatment selection for head and neck cancer requires survival models that use routine clinical variables while accounting for censored time-to-event outcomes. This study developed an interpretable Cox proportional hazards baseline and a DeepSurv framework to estimate mortality risk and explore treatment-specific predictions among radiotherapy-based options. Methods: Clinical data were obtained from the RADCURE collection in The Cancer Imaging Archive. After preprocessing, stage harmonization, exclusion of sparse treatment categories, missing-data assessment, one-hot encoding, and standardization, 3266 patients were analyzed. Cox regression and DeepSurv were evaluated using a held-out 80%/20% split, paired bootstrap confidence intervals for C-index differences, and five-fold cross-validation. For treatment recommendation, treatment modality was hypothetically varied across radiotherapy alone, chemoradiotherapy, and radiotherapy plus epidermal growth factor receptor inhibitor while other covariates were held fixed. Results: On the held-out test set, Cox achieved a C-index of 0.684 and DeepSurv achieved a C-index of 0.695. The absolute difference was 0.011, with a paired bootstrap 95% CI of −0.010 to 0.030, indicating no statistically significant improvement. Five-fold cross-validation showed mean C-index values of 0.688 for Cox and 0.707 for DeepSurv. Cox regression identified older age and advanced tumor stage as higher-risk factors, whereas former and non-smoking status were associated with lower hazard than current smoking. Conclusions: DeepSurv provided only a modest numerical gain over the Cox baseline. The recommendation framework illustrates how survival models can generate treatment-specific risk estimates, but these outputs should be interpreted as decision-support signals rather than causal treatment effects. External validation and prospective evaluation are needed before clinical use. Full article

Background/Objectives: 2-(2-Benzofuranyl)-2-imidazoline (2-BFI) is a selective imidazoline I₂-site ligand that has shown neuroprotective and neuromodulatory effects in preclinical central nervous system (CNS) studies. However, the primary preclinical literature remains fragmented across disease models, outcome types, mechanistic endpoints, and cellular targets, making it difficult to define where its therapeutic-development potential is strongest and how disease- or model-specific functional effects relate to molecular, cellular, tissue, and blood–brain barrier/neurovascular unit (BBB/NVU)-related findings. Methods: This systematic review integrated preclinical evidence from 36 original studies identified in the PubMed, Web of Science, Embase, and Scopus databases through searches last updated on May 19, 2026, to evaluate the strength of evidence for 2-BFI across CNS-related models and to connect functional, molecular, cellular, and neurovascular findings. The evidence categories included ischemic stroke/neurovascular outcomes (n = 13), traumatic CNS injury (n = 2), neuroinflammatory/neurodegeneration-related models (n = 9), behavioral pharmacology (n = 8), and cellular mechanisms (n = 4). Eligible studies were original CNS-related animal, cellular, or behavioral/pharmacological studies that directly evaluated 2-BFI and reported neuroprotective, neurological, cellular, molecular, vascular, inflammatory, neurotransmitter-related, or behavioral outcomes. Findings were synthesized qualitatively, and risk of bias in in vivo animal studies was assessed using SYRCLE’s risk-of-bias tool. Results: The most extensive preclinical evidence was found in ischemic stroke and neurovascular injury models, in which 2-BFI attenuated infarct size, neurological deficits, and edema, and suppressed apoptosis-related injury and blood–brain barrier/neurovascular unit (BBB/NVU) disruption. Across models, these effects are best interpreted as modulation of interconnected secondary injury processes involving N-methyl-D-aspartate receptor (NMDAR)/Ca²⁺-dependent excitotoxicity, oxidative and mitochondrial stress, inflammatory amplification, regulated cell death, and neurovascular destabilization. Evidence from traumatic CNS injury, autoimmune neuroinflammation, Alzheimer’s disease-related models, chronic epilepsy, and cellular stress models broadened the CNS relevance of 2-BFI but remained less replicated or more mechanistically indirect than the stroke/neurovascular evidence. Behavioral and pharmacological studies additionally indicated that 2-BFI modulates neurotransmitter-related systems associated with pain-, affective-, addiction-, opioid-, and compulsivity-related outcomes, although these findings should be distinguished from disease-modifying neuroprotective evidence. Conclusions: Meta-analysis was not conducted because of heterogeneity in models, dosing regimens, treatment timing, and outcomes. Overall, the current evidence does not yet support definitive dosing, treatment timing, or clinical development recommendations for 2-BFI. The strongest preclinical therapeutic rationale is currently found in ischemic stroke and neurovascular injury settings, whereas other CNS indications require further validation. Future studies should define dose–response relationships, therapeutic windows, pharmacokinetic and safety profiles, sex- and age-related effects, and efficacy in clinically relevant comorbid models before clinical translation is considered. The review was not prospectively registered. Funding was provided by a National Research Foundation of Korea grant funded by the Korean government. Full article

Background: Current treatments for myasthenia gravis (MG), while improving outcomes, are often associated with adverse effects, and a proportion of patients remain refractory to standard therapies. Eculizumab, a humanized monoclonal antibody targeting complement protein C5, is approved for refractory anti-acetylcholine receptor antibody-positive generalized MG (AChR-Ab+ gMG). Aim of the present study is to explore the rapidity of onset of eculizumab efficacy in a single-center cohort of MG patients. Methods: This retrospective, observational, single-center study evaluated the real-world effectiveness and rapidity of response to eculizumab in patients with AChR-Ab+ gMG. Patients received eculizumab according to the approved regimen and were assessed at baseline (T0), 5 weeks (T1), and 3 months (T2) using the Myasthenia Gravis Activities of Daily Living (MG-ADL) score, Quantitative Myasthenia Gravis (QMG) score, and Myasthenia Gravis Foundation of America (MGFA) classification. Results: Eight patients were eligible for the study with a mean age of 73.1 years. A rapid clinical improvement was observed after treatment initiation. Mean MG-ADL scores decreased from 8.38 at T0 to 2.13 at T1 (p < 0.001; Cohen’s d = 2.075), while QMG scores declined from 13.75 to 5.63 (p = 0.001; Cohen’s d = 1.824). Improvements were maintained at T2. Mean percentage reductions from T0 to T1 were 73.5% for MG-ADL and 60.6% for QMG. Eculizumab was well tolerated. Conclusions: These real-world findings confirm a rapid and clinically meaningful response to eculizumab in elderly patients with refractory gMG. These findings highlight its potential role in achieving early symptom control and reducing disease burden in this clinically vulnerable population. Full article

Background: Endotoxemia is a severe inflammatory condition that is characterized by acute immune responses and oxidative stress; endotoxemia can further develop into a cytokine storm and sepsis leading to severe organ damage. Our recent studies revealed that the growth hormone secretagogue receptor (GHSR) regulates macrophage polarization in obesity- and aging-associated chronic inflammation. However, its role in acute inflammation during endotoxemia remains unclear. Methods: We subjected myeloid-specific Ghsr knockout mice (LysM-Cre;Ghsr^f/f) to lipopolysaccharide (LPS)-induced endotoxemia in vivo and treated bone marrow-derived macrophages (BMDMs) with LPS in vitro. Subsequently, mouse survival rate and inflammatory signatures in the blood, peritoneal cavity, liver, and BMDM were assessed. In the ex vivo study, conditioned medium (CM) from BMDMs was applied to primary hepatocytes to assess how BMDM-derived CM influences hepatocyte inflammatory responses. Results: Myeloid-specific Ghsr knockout mice exhibited a significantly improved survival rate following LPS-induced endotoxemia, accompanied by reduced systemic inflammation, evident in the blood, peritoneal macrophages, and liver. In addition, Ghsr deficiency suppressed LPS-induced caspase-1 activation and pro-inflammatory cytokine secretion in macrophages. Consistent with these results, conditioned media from Ghsr-deficient BMDMs attenuated the inflammatory responses of primary hepatocytes. Mechanistically, LPS increased GHSR expression in BMDMs, and Ghsr-deficient BMDMs activated mitochondrial respiration and suppressed production of mitochondrial reactive oxygen species (ROS), resulting in downregulation of inflammatory activation of macrophages following LPS exposure. Conclusions: These data demonstrate that macrophage GHSR promotes systemic and tissue inflammation during endotoxemia by regulating mitochondria-associated macrophage polarization. The findings suggest that macrophage GHSR may represent a promising immunomodulatory target for acute inflammatory states, including endotoxemia and sepsis. Full article

Purpose: Hypertension in women is a dynamic, hormone sensitive condition shaped by cumulative physiological changes across the life course. This review summarises current evidence relating vascular ageing, hormonal regulation, metabolic dysfunction, and reproductive history to blood pressure regulation in women. Materials and Methods: A narrative review of the literature was conducted using PubMed, Scopus and Google Scholar. Clinical, epidemiological, and mechanistic studies were synthesised to evaluate factors influencing hypertension in women. Reports in which menopausal status was not defined, or previous reproductive milestones were not documented, were excluded or interpreted with caution. Results: Evidence suggests that menopause, vascular ageing, metabolic dysfunction, androgen to oestrogen balance, and reproductive history interact to influence endothelial function, neurohormonal regulation, renal sodium handling, and vascular resistance. Ageing-related mechanisms, including cellular senescence, chronic low-grade inflammation, and genetic susceptibility, may contribute to increased cardiovascular risk. Hypertensive disorders of pregnancy identify women who are at higher risk of developing cardiovascular disease later in life and provide an opportunity for earlier risk assessment and prevention. Emerging therapies, including GLP-1 receptor agonists and SGLT2 inhibitors, may offer additional options for improving cardiovascular risk management, although their role in sex-specific prevention remains an evolving area of research. Conclusions: Hypertension in women is best understood within a life-course framework. Incorporating reproductive history, menopausal status, metabolic health, and emerging risk markers may improve cardiovascular risk assessment and support earlier intervention. Full article

Background: Autoimmune diseases (AIDs) are associated with increased cardiovascular risk. However, specific protein mediators linking AIDs to major adverse cardiovascular events (MACE) and cardiovascular death (CV death) remain unexplored. This study identifies proteomic mediators linking AIDs to MACE via high-dimensional mediation analysis in the UK Biobank. Methods: We used UK Biobank data with proteomic profiling by Olink platform. Participants with prevalent myocardial infarction (MI), stroke, and heart failure at baseline were excluded. AIDs were categorized into musculoskeletal (MSK), vasculitis, gastrointestinal (GI), neurologic, and rheumatic fever subsets. Fine–Gray models assessed associations between AIDs and MACE and CV death. Proteome-wide association studies identified proteins associated with both AIDs and cardiovascular outcomes. High-dimensional mediation analysis (HIMA) explored protein-mediated pathways. All models adjusted for age, sex, lipids, BMI, smoking, hypertension, diabetes, chronic kidney disease, atrial fibrillation, and coronary artery disease. Results: Among 400,633 participants (median follow-up 14.5 years, 44.8% male), AIDs were present in 28,754 (7.2%). All AID categories were associated with increased MACE (sHR: MSK 1.34, vasculitis 1.67, GI 1.20, neurologic 1.33, rheumatic fever 1.38; all p < 0.001). For CV death, MSK, vasculitis, and rheumatic fever showed increased risk (sHR 1.34, 1.78, 1.51; all p ≤ 0.004), but not GI or neurologic AIDs. In 43,599 participants with proteomic data, HIMA identified 66 and 32 unique potential mediators linking AIDs to MACE and CV death, respectively. Four proteins (Growth Differentiation Factor 15, Interleukin-15, urokinase plasminogen activator receptor, and Tenascin C) mediated the AID-MACE relationship across multiple AID categories. Growth Differentiation Factor 15 and Interleukin-15 were shared mediators for CV death. Conclusions: This proteomic analysis identifies specific proteins that may mediate the association between AIDs and adverse cardiovascular outcomes, offering mechanistic insights into immune-related cardiovascular risk. These findings are hypothesis-generating and require replication and validation before the identified proteins can be considered causal mediators or adopted for clinical risk stratification. Full article

Menthol is an agonist of TRPM8 receptors that activates tear secretion. Objectives: The hypothesis was that menthol delivered to the cornea in vapor form could stimulate tear secretion without irritation. Methods: This was a randomized, placebo-controlled, double-blind clinical trial of menthol vapor. Thirty generally healthy participants were randomized to the treatment or placebo group. Results: Median age was 58 (43, 73 IQR) years, 18 participants (60%) were female; 12 (40%) were male. Tear weight exceeded 5 mg in 2 (13.3%) of the placebo group, versus 13 (86.7%) of the menthol group (p = 0.020). Median weight of tears wiped from below the eye in the placebo group was 3 (−1, 8 IQR) mg versus 13 (8, 35 IQR) mg in the menthol group (p = 0.002). Nasolacrimal drainage in the placebo group weighed 10 (4,12 IQR) mg versus 56 (22, 173 IQR) mg in the menthol group (p < 0.001). The treated right eye felt qualitatively moister than the untreated left eye in 7 (47%) of the placebo group, versus 15 (100%) of the menthol group (p = 0.002). No participant reported eye irritation or any adverse effects at the one-week follow-up. Conclusions: Menthol delivered to the eye as vapor evoked tear secretion without eye irritation. Menthol vapor warrants further study as a complementary treatment or an alternative to eye drops for dry eye disease. Full article

(1) Fibromyalgia syndrome (FMS) is a chronic pain disorder with a multifactorial pathogenesis involving neuroinflammation, oxidative stress, and immune dysfunction. This study aimed to evaluate serum biomarkers related to purinergic signaling, inflammasome activation, pyroptosis, and oxidative stress in patients with FMS. (2) Methods: A total of 93 patients with FMS and 93 age- and sex-matched healthy controls were enrolled. Serum levels of pannexin-1 (PANX1), purinergic receptor P2X7 (P2RX7), NLRP3, caspase-1 (CASP1), interleukin-1β (IL-1β), interleukin-18 (IL-18), gasdermin D (GSDMD), and gasdermin E (GSDME) were measured using enzyme-linked immunosorbent assays (ELISA). (3) Results: Total antioxidant status (TAS) and total oxidant status (TOS) were determined. Patients with FMS exhibited significantly increased serum CASP1, GSDME, PANX1, P2RX7, and total oxidative stress (TOS) levels, whereas GSDMD, NLRP3, IL-18, and TAS levels were significantly decreased compared with controls (all p < 0.05). No significant differences were observed in IL-1β levels. Receiver operating characteristic analysis demonstrated exploratory discriminatory performance within this case–control cohort for CASP1 and TAS (AUC = 0.898), followed by TOS (AUC = 0.849) and P2RX7 (AUC = 0.757). (4) Conclusions: These findings indicate alterations in circulating biomarkers related to purinergic signaling, inflammasome-associated pathways, pyroptosis-related proteins, and oxidative stress in patients with FMS. These alterations may contribute to the pathophysiology of FMS and provide a foundation for future mechanistic studies investigating their potential as biomarkers and therapeutic targets. Full article

Aging is driven by progressive epigenetic alterations—DNA methylation drift, aberrant histone modifications, chromatin remodeling, and non-coding RNA dysregulation. Vitamin D, acting through its nuclear receptor vitamin D receptor (VDR), modulates the epigenetic landscape to potentially counteract these age-related changes. This review first describes age-related epigenetic alterations, then outlines vitamin D signaling and its interface with the epigenetic machinery. Next, tissue-specific epigenetic actions of vitamin D in the immune, musculoskeletal, and nervous systems are discussed. Finally, clinical trial evidence is examined, interindividual variability is highlighted, and future research directions are proposed. However, large randomized controlled trials (RCTs) consistently show limited benefits of vitamin D monotherapy, with measurable anti-aging effects observed when combined with exercise and nutritional interventions. Its efficacy is constrained by interindividual variability, J-shaped dose–response, and tissue-specific barriers. For deficient individuals (serum 25-hydroxyvitamin D (25(OH)D) < 50 nmol/L), guided supplementation—typically 800–2000 international units (IU)/day—is warranted to achieve tentative target serum concentrations of 75–125 nmol/L, the range linked to favorable epigenetic and immune effects. For those already sufficient (e.g., serum 25(OH)D ≥ 50 nmol/L), indiscriminate supplementation without biochemical indication is not supported. Therefore, promoting healthy aging through vitamin D requires serum-monitored, individually titrated, and multimodal regimens, with supplementation reserved primarily for documented deficiency and integrated with lifestyle interventions. Full article

The vitamin D receptor (VDR) exerts pleiotropic effects essential for human health and modulates the transcription of nuclear factor erythroid 2-related factor 2 (Nrf2), a key regulator of the cellular antioxidant defense system. Polymorphisms represent a major source of interindividual variability and may influence susceptibility to oxidative stress. The VDR polymorphisms ApaI (A > C) and TaqI (T > C) have been associated with disease susceptibility; however, their role in oxidative stress responses during aging remains poorly understood. This study evaluated the association between ApaI and TaqI polymorphisms and susceptibility to oxidative stress-induced cell death, as well as the expression of genes within the VDR–Nrf2 signaling axis, in peripheral blood mononuclear cells (PBMCs) from cognitively healthy Chilean older adults. VDR genotyping was performed using real-time PCR (TaqMan SNP Genotyping Assay), PBMC viability following H₂O₂ exposure was assessed by flow cytometry, and gene expression levels were determined by quantitative PCR (qPCR). For ApaI, homozygous carriers of the A allele showed greater PBMC viability following H₂O₂ exposure (p < 0.0068) and higher mRNA expression levels of Nrf2 (p = 0.0176) and its downstream genes HMOX1 (p = 0.0070) and GST (p = 0.0047) compared with carriers of the C allele (AC or CC). For TaqI, homozygous carriers of the protective C allele exhibited greater PBMC viability (p < 0.0465) and higher Nrf2 (p = 0.0324), HMOX1 (p = 0.0206), and GST (p = 0.0029) expression compared with carriers of the risk T allele (TC or TT). These findings provide novel evidence that VDR polymorphisms may modulate antioxidant responses through regulation of Nrf2-dependent gene expression, suggesting a genetic determinant of oxidative stress resilience in cognitively healthy older adults. Full article

Background/Objectives: Sensory nerves, as essential peripheral nerves, innervate bone and release various neuroactive substances—including neurotransmitters, neuropeptides, and neurocrine factors—that participate in bone growth, remodeling, and metabolism. Interleukin-1 receptor antagonist (IL1RN), an endogenous anti-inflammatory mediator, is a key regulatory molecule in the pathogenesis of inflammatory diseases such as osteoarthritis and rheumatoid arthritis. However, its role as a sensory neurocrine factor in the regulation of bone tissue has rarely been investigated. This study aimed to explore the regulatory effects of sensory nerve–derived IL1RN on bone tissue. Methods: A dorsal root ganglion (DRG)-targeted delivery system was developed using DNA origami technology to load IL1RN protein or IL1RN-targeting siRNA and was functionalized with a DRG-homing peptide. Bone defect and age-related bone loss models were established in C57BL/6 mice to preliminarily investigate the regulatory role of IL1RN secreted from sensory nerve endings in bone tissue. Results: IL1RN suppressed bone resorption and promoted new bone formation at defect sites. In the age-related bone loss model, IL1RN preserved the integrity of the growth plate. These findings indicate that sensory nerve–derived IL1RN may participate in the regulation of bone repair and skeletal homeostasis. Conclusions: IL1RN may serve as a potential therapeutic target for DRG-mediated regulation of bone repair. These findings suggest that DRG-targeted modulation of IL1RN may represent a potential approach for investigating and regulating sensory nerve–associated bone repair. Full article

Background/Objectives: To evaluate whether the combination of oral eplerenone and half-dose full-fluence photodynamic therapy (HD-FF PDT) provides greater efficacy than HD-FF PDT alone in persistent central serous chorioretinopathy (CSCR). Methods: This monocentric, retrospective, observational study included patients with persistent (>6 months) simple or complex CSCR who had previously undergone either half-dose full-fluence photodynamic therapy (HD-FF PDT) alone or HD-FF PDT combined with oral eplerenone as part of routine clinical practice between September 2024 and March 2025. Functional and morphological data collected at baseline and at 1, 3, and 6 months after treatment were retrospectively reviewed. An artificial intelligence–based algorithm was used to analyze OCT scans, quantifying subretinal and intraretinal fluid volumes (SRFV, IRFV) and assessing ellipsoid zone and external limiting membrane integrity, hyperreflective foci, subfoveal choroidal thickness (SCT), and central macular thickness (CMT). Results: Fifty patients (53 eyes; mean age 52 years) were included, with no significant baseline differences between groups. Best-corrected visual acuity improved more significantly in Group B at 1 and 6 months (p = 0.032 and p = 0.009, respectively). At 6 months, subretinal fluid volume (SRFV), quantified by AI-based OCT analysis, was significantly lower in the combined therapy group (p = 0.014). An AI-defined complete resolution of subretinal fluid (SRFV < 0.010 mm³) was achieved more frequently in Group B than in Group A (77% vs. 22%, p = 0.001). Conclusions: Although HD-FF PDT remains the standard treatment for persistent CSCR, adjunctive therapy with the mineralocorticoid receptor antagonist eplerenone may enhance subretinal fluid reabsorption and improve mid-term anatomical and functional outcomes. Full article