Search Results (3,401)

Transcranial magnetic stimulation (TMS) is a non-invasive brain stimulation method with neuromodulatory capacity in neurodegenerative diseases such as multiple sclerosis (MS). Its therapeutic value is linked to its activity against oxidative stress by activation of antioxidant defenses. The sex hormones, estrogens (E), progesterone (P) and testosterone (T), have demonstrated their power as adjuvants to TMS, improving cortical excitability. The aim of this study was to evaluate the effect of these hormones as adjuvants to extremely low-frequency electromagnetic fields (ELFEFs) in the treatment of experimental autoimmune encephalomyelitis (EAE), the experimental model of MS. The effect of these hormones as replacement therapy was also evaluated in ovariectomized rats treated with ELFEFs. Sixty-five female Dark Agouti rats were divided into 13 groups (5 rats/group), in which biomarkers of oxidative stress and the glutathione redox cycle in non-nervous organs (kidney, liver, heart, intestines and blood) were analyzed. The results show that ELFEFs alone are more effective against oxidative stress. However, P and E were more effective than ELFEFs, both as adjuvants and in hormone replacement therapy, in activating the glutathione system. Therefore, it could be concluded that sex hormones play an important role against MS, enhancing the antioxidant effect of ELFEFs. Full article

Lutetium-177-PSMA-617 (Lu-PSMA) radioligand therapy (RLT) is established in metastatic castration-resistant prostate cancer (mCRPC), with regulatory approvals based on the VISION and TheraP trials. Subsequent trials have extended the evidence to taxane-naive mCRPC (PSMAfore) and demonstrated that combining Lu-PSMA with enzalutamide yields a significant overall survival benefit over enzalutamide alone (ENZA-p). However, higher and more homogeneous PSMA expression in treatment-naive disease, combined with lower tumor burden and preserved bone marrow reserve, provides a biological rationale for deploying RLT earlier in the disease course. In metastatic hormone-sensitive prostate cancer (mHSPC), the Phase III PSMAddition trial reported improved radiographic progression-free survival when Lu-PSMA was added to standard androgen deprivation therapy (ADT) plus androgen receptor pathway inhibitor (ARPI), and the Phase II UpFrontPSMA trial demonstrated enhanced biochemical responses with Lu-PSMA induction before docetaxel. In oligometastatic and oligorecurrent disease, the BULLSEYE and LUNAR trials have shown progression-free survival benefits, raising the possibility of deferring androgen deprivation therapy and its associated morbidity. Meanwhile, next-generation radionuclides, including actinium-225 (WARMTH) and the dual beta-Auger emitter terbium-161 (VIOLET), are entering clinical development to address the radiobiological limitations of Lutetium-177. This review synthesizes the evidence for PSMA-targeted radioligand therapy across the prostate cancer disease continuum and discusses patient selection, treatment sequencing, and the access and cost-effectiveness considerations that will shape adoption in earlier disease settings. Full article

This narrative review examines perimenopause as a critical transitional phase in women’s lives, often accompanied by elevated vulnerability to anxiety and depression. Dysfunction of the gut–brain axis is one of the key factors contributing to perimenopausal mood disorders and is currently receiving extensive attention. GBA dysfunction can trigger neurotransmitter metabolic imbalance, intestinal barrier impairment, and neuroinflammatory responses. Tryptophan (Trp) and γ-aminobutyric acid (GABA) serve as essential precursors and direct modulators of key neurotransmitters, and the dysregulation of their metabolic pathways has been implicated in perimenopausal anxiety and depression in animal models and limited clinical observations. Trp influences 5-hydroxytryptamine (5-HT) by affecting emotional states. GABA is the primary inhibitory neurotransmitter in the central nervous system and is closely associated with anxiety and depression. Fluctuations in estrogen levels during perimenopause significantly alter the composition and metabolic activity of the gut microbiota, which in turn affects Trp metabolism and GABA synthesis through increased intestinal permeability, activation of immune-inflammatory responses, and disruption of hypothalamic–pituitary–adrenal (HPA) axis function. Although traditional hormone replacement therapy and pharmacological treatments are effective, they are associated with some side effects. Preliminary evidence from in vitro and animal studies suggests that nutritional interventions targeting Trp and GABA metabolism within the gut–brain axis may offer a novel research direction, though their efficacy in perimenopausal women remains to be established. Potential nutritional strategies, including supplementation with Trp and its precursors, inhibition of the kynurenine pathway (KP), and supplementation with probiotics and prebiotics, can modulate Trp and GABA metabolism. This review focuses on Trp and GABA metabolic regulation via the gut–brain axis to explore pathogenesis of perimenopausal anxiety and depression and summarize potential nutritional intervention targets, thereby providing a scientific basis for emotional management in perimenopausal women. Full article

Structural and functional disruptions of the epigenome are hallmarks of breast and ovarian carcinogenesis. This review dissects the reciprocal regulatory networks co-operated by DNA methyltransferases (DNMTs), ten-eleven translocation enzymes (TETs), and key non-coding RNAs (microRNAs and lncRNAs). We map the precise molecular mechanisms through which these epigenetic modulators alter chromatin accessibility, drive transcriptional reprogramming, and promote phenotypic plasticity in hormone-dependent malignancies. By systematically contrasting the distinct yet overlapping epigenetic profiles of breast and ovarian tumors, we elucidate how these aberrations dictate clinical outcomes. This comprehensive synthesis offers critical insights into the dual utility of these epigenetic elements as dual-purpose diagnostic biomarkers and druggable therapeutic targets, laying the groundwork for next-generation targeted epigenetical therapies. Full article

Purpose: Tertiary hyperparathyroidism is a frequent complication of end-stage kidney disease that may require parathyroidectomy when medical therapy fails. Recurrent hyperparathyroidism may occur after total parathyroidectomy with autotransplantation. This study assessed the safety, feasibility, and efficacy of percutaneous ultrasound-guided ablation for implanted parathyroid glands in patients with recurrent disease after total parathyroidectomy with autotransplantation. Materials and Methods: Eleven patients with recurrent hyperparathyroidism following total parathyroidectomy with autotransplantation who underwent percutaneous ultrasound-guided ablation were retrospectively reviewed. Pre- and post-procedure serum intact parathyroid hormone, calcium, phosphate, and alkaline phosphatase levels were extracted from electronic medical records and analyzed. Ablation modalities used in the study included radiofrequency ablation, microwave ablation, and cryoablation. Procedure-related complications were recorded. Patients were followed for 12 months with serial biomarker monitoring. Technical success was defined as ≥80% ablation of implanted parathyroid glands, and clinical success as meeting at least two of the following: (1) >50% intact parathyroid hormone reduction, (2) correction of hypercalcemia, (3) discontinuation of calcimimetic therapy. Results: Technical success was achieved in 10 of 11 (90.9%) patients; one patient had incomplete ablation due to proximity of the gland to the skin. Among technically successful cases, all (100%) achieved clinical success, showing marked decreases in intact parathyroid hormone, normalization of calcium and phosphate, and reduced calcimimetic use. Transient hypocalcemia occurred in six patients, five requiring intravenous calcium replacement. No long-term complications were observed. Conclusions: Percutaneous ultrasound-guided ablation of implanted parathyroid glands is a safe and effective option for managing recurrent hyperparathyroidism, offering a viable alternative to surgery. Full article

Background/Objectives: Treatment intensification with novel hormonal therapies is now standard in metastatic hormone-sensitive prostate cancer (mHSPC), but real-world patients are often more heterogeneous than those included in pivotal trials. This study aimed to describe clinical characteristics, safety, treatment discontinuation, disease progression, polypharmacy, and clinically documented drug–drug interactions in a real-world mHSPC cohort. Methods: We conducted a retrospective observational study including 109 patients with mHSPC who initiated abiraterone, enzalutamide, apalutamide, or docetaxel-based triplet regimens between January 2015 and November 2025. Outcomes included adverse events, discontinuation, PSA50 response at 3 months, time to progression and overall survival. Descriptive analyses and Kaplan–Meier estimates were performed. Results: Apalutamide was the most frequent first-line treatment (56.9%), followed by abiraterone (23.9%), enzalutamide (11.9%), darolutamide-based triplet therapy (3.7%), and abiraterone-based triplet therapy (3.7%). Median age was 73 years, and median baseline PSA was 16.1 ng/mL. De novo metastatic disease was present in 69.7% of patients, ISUP grade 4–5 disease in 58.7%, high-risk disease according to LATITUDE criteria in 45.9%, and high-volume disease according to CHAARTED criteria in 38.5%. The median Charlson Comorbidity Index was 4, and polypharmacy was observed in 68.8%. Adverse events occurred in 56.0%, and non-death treatment discontinuation occurred in 22.0%. No documented drug–drug interactions requiring treatment modification were recorded. PSA50 response was achieved by 97.2%. Thirteen patients (11.9%) progressed and 18 (16.5%) died. Median time to progression was not reached, and median overall survival was 53.2 months. Conclusions: Novel hormonal therapies were used in a clinically heterogeneous real-world mHSPC cohort. The findings support individualized treatment assessment and should be interpreted as descriptive and exploratory. Full article

Background/Objectives: The global landscape of growth hormone (GH) therapy is increasingly affected by supply shortages, posing risks to treatment continuity, particularly in rare diseases with a single authorized GH brand. In Italy, a prolonged shortage of the only approved recombinant human GH (rhGH) for SHOX-deficient (SHOXD) patients (Somatropin, Humatrope^®) raised concerns about treatment interruption. As growth impairment is a key clinical feature of SHOXD, uninterrupted rhGH therapy is essential. To address this issue, the Italian Medicines Agency (AIFA) temporarily authorized the off-label use of alternative rhGH formulations. This study aimed to evaluate growth outcomes and safety over one year of off-label rhGH treatment in SHOXD patients and to compare these data with prior Humatrope^® treatment. Methods: Fifty SHOXD patients (25 females), aged 2–17 and still in the growth phase, previously treated with Humatrope^®, were switched to an alternative rhGH therapy. Height standard deviation scores (HSDS) and height velocity standard deviation scores (HVSDS) were recorded 12 and 6 months before and after the switch. Growth trends were analyzed using repeated-measures ANOVA. Results: No statistically significant differences in HSDS or HVSDS were observed after switching to alternative rhGH compared with prior treatment (p > 0.05). IGF-1 SDS values remained stable within age- and puberty-appropriate reference ranges. No adverse events were reported. Conclusions: In this real-world pediatric cohort, one year of off-label rhGH treatment during a drug shortage was not associated with relevant changes in growth parameters or safety concerns. These findings may support treatment continuity during temporary disruptions in rhGH availability. Full article

Objective: Thyroid hormone treatment is the standard therapy for hypothyroidism, particularly in women. Concerns have been raised that exogenous thyroid hormone use may increase breast cancer risk, but evidence remains inconclusive. This study aimed to systematically review and synthesize observational evidence on the association between thyroid hormone treatment and breast cancer risk in women. Design: We conducted a systematic review and meta-analysis of observational studies. Methods: MEDLINE, EMBASE, and Web of Science were searched from January 1976 to February 2025. Eligible studies assessed breast cancer incidence in adult women receiving thyroid hormone treatment versus non-users. Pooled ORs were calculated. Findings from cohort studies reporting hazard ratios were synthesized qualitatively. Heterogeneity, publication bias, and certainty of evidence were assessed. PROSPERO ID: CRD42022348966. Results: Four case–control studies including 221,254 women receiving thyroid hormone treatment and 4,385,666 controls were included in the prespecified primary OR-based meta-analysis. In the primary random-effects meta-analysis, thyroid hormone treatment showed a possible epidemiological signal with breast cancer risk (OR 1.43, 95% CI: 0.90–2.28; I² = 94.3%), although the confidence interval crossed unity and heterogeneity was substantial. Formal assessment of publication bias was performed but should be interpreted cautiously given the small number of included studies. The certainty of evidence was rated as low due to heterogeneity, serious inconsistency and imprecision. Conclusions: Thyroid hormone treatment was associated with a possible epidemiological signal for breast cancer in observational studies; however, the primary pooled estimate was not statistically significant and should be interpreted as hypothesis-generating because of substantial heterogeneity and residual confounding. Further well-designed prospective studies are required before causal or clinical inferences can be made. Full article

Background: Comparative oncology uses naturally occurring cancers in companion animals to study tumor biology and therapeutic responses relevant to human cancer. Spontaneous feline tumors are increasingly recognized as useful comparative models because they arise in immunocompetent hosts, develop under shared environmental exposures, and can reproduce selected clinical, histopathologic, molecular, and therapeutic features of human malignancies. Methods: This review compares feline oral squamous cell carcinoma (FOSCC) with human head and neck squamous cell carcinoma (HNSCC), and feline mammary carcinoma (FMC) with human breast cancer, emphasizing shared pathologic, molecular, tumor microenvironment, and therapeutic features. Results: Recent immunohistochemical, genomic, transcriptomic, and biomarker studies have identified shared features between feline and human cancers. FOSCC resembles human HNSCC through aggressive local invasion, histologic features, therapeutic resistance, and recurrent alterations of TP53, MYC, and PTEN. FMC shows strong overlap with aggressive human triple-negative breast cancer, including reduced hormone receptor expression, recurrent TP53, PIK3CA, and CXCL12/CXCR4 signaling alterations, and tumor microenvironment features involving immune-checkpoint, inflammatory, and angiogenic pathways. FOSCC clinical trials and emerging clinical investigations into FMC treatments further support the use of cats for translational therapy evaluation. Conclusions: FOSCC and FMC are promising comparative oncology models for human HNSCC and aggressive breast cancer, respectively. Future multicenter studies incorporating standardized tumor classification and grading, predefined stratification criteria, and clinically meaningful endpoints will be essential to strengthen their translational value. Full article

Background/Objectives: Breast cancer is the most commonly diagnosed malignancy among women, with hormone receptor-positive tumors representing the majority of cases. Increasing survival rates have shifted attention toward long-term complications, including the risk of secondary malignancies. Emerging evidence suggests a potential association between breast cancer and gastrointestinal (GI) neoplasia. This study aimed to evaluate the role of colonoscopic and upper gastrointestinal endoscopic monitoring in patients with ER/PR-positive breast cancer and to assess its potential value in the early detection of digestive lesions. Methods: We conducted a prospective observational study including 186 female patients with histologically confirmed ER/PR-positive breast cancer. A total of 95 patients underwent colonoscopy, and 91 patients underwent upper gastrointestinal endoscopy. Clinical, demographic, and risk factor data were collected. A structured questionnaire was used to assess gastrointestinal symptoms. Endoscopic findings, lesion characteristics, and histopathological results were recorded. Bowel preparation quality was assessed using the Boston Bowel Preparation Scale. Results: Colonoscopy identified polyps and other lesions, with the majority located in the rectum and descending colon. A total of 12 biopsies were performed, revealing 1 malignant lesion, 2 borderline lesions, and the remainder benign. Upper gastrointestinal endoscopy showed gastritis as the most frequent finding, followed by gastric ulcers and polyps, while most patients had normal endoscopic results. Overall, 72% of patients presented at least one risk factor for digestive malignancy. Following treatment, most patients reported improvement in gastrointestinal symptoms. Conclusions: Patients with ER/PR-positive breast cancer may present a higher prevalence of gastrointestinal lesions, potentially related to shared risk factors and the systemic effects of endocrine therapy. Targeted, symptom-oriented endoscopic evaluation may facilitate early detection of premalignant and malignant digestive conditions. A multidisciplinary, risk-adapted surveillance approach should be considered to improve patient outcomes. Further large-scale studies are required to establish evidence-based screening strategies in this population. Full article

Uridine diphosphate glucuronosyltransferase 2B (UGT2B) enzymes constitute a critical subgroup of phase II metabolizing enzymes that modulate the clearance of steroid hormones, carcinogens, and numerous anticancer agents, thereby influencing cancer susceptibility, progression, and therapeutic outcomes. This review provides a comprehensive synthesis of the genetic, regulatory, and functional roles of UGT2B family members, particularly UGT2B4, UGT2B7, UGT2B10, UGT2B15, UGT2B17, and UGT2B28, in oncogenesis and cancer treatment. We summarize evidence from molecular, epidemiological, pharmacogenetic, and clinical studies demonstrating how UGT2B expression patterns, polymorphisms, copy number variations, epigenetic regulation, and microRNA-mediated control shape intratumoral hormone homeostasis, carcinogen detoxification, and drug resistance across multiple malignancies, including prostate, breast, lung, colorectal, hematological, and hormone-dependent cancers. UGT2B enzymes metabolize several widely used anticancer drugs and active metabolites, thereby affecting pharmacokinetics, efficacy, and toxicity. Understanding the context-specific roles of UGT2B family members offers a compelling opportunity for therapeutic exploitation. In particular, rational combination strategies incorporating UGT2B inhibitors or modulators alongside standard anticancer agents may enhance drug effectiveness without increasing dosage, while simultaneously enabling the dose reduction of the partner agent to mitigate dose-dependent toxicities. Such approaches are especially relevant for therapies with narrow therapeutic indices. Overall, this review highlights UGT2B enzymes as multifunctional determinants of cancer risk and treatment response and underscores their promise as biomarkers and actionable targets for precision oncology and optimized combination regimens. Full article

Background: Breast cancer is the most common malignancy among women and a leading cause of cancer-related deaths globally. Its development involves hormonal, genetic, environmental and inflammatory factors. Among environmental contributors, cadmium (Cd²⁺), a metalloestrogen known to induce redox imbalance, as well as estrogen metabolites, may exert divergent biological effects. Methods: This study investigated the effects of 17β-estradiol (E2) and its metabolites—2-methoxyestradiol (2-MeOE2) and 4-hydroxyestradiol (4-OHE2)—administered alone or in combination with CdCl₂, on estrogen receptor–-positive MCF-7 breast cancer cells and their doxorubicin-resistant cells (MCF-7/DOX). We evaluated cytotoxicity, interaction profiles (synergism/antagonism), and redox-related enzymes associated with drug resistance, including superoxide dismutase 1 (SOD1) and glutathione S-transferase pi (GST-pi). There are no known examples of these types of interactions, especially those involving estrogen metabolites with opposing biological activities—anticancer 2-MeOE2 and procarcinogenic—4-OHE2 in combination with cadmium. Cell viability was assessed after 48 h exposure to individual and combined treatments of CdCl₂. Interaction types (synergism/antagonism) were determined via the combination index method. Antioxidative enzymes were evaluated by quantitative and immunocytochemical analysis of SOD1, GST and GST-pi expression. Results: All tested compounds reduced cell viability in a concentration-dependent manner, with CdCl₂ showing the highest cytotoxicity. MCF-7 cell lines were generally more sensitive to CdCl₂, E2, and 2-MeOE2, whereas MCF-7/DOX cell lines exhibited greater sensitivity to 4-OHE2. Combination studies revealed predominantly antagonistic interactions, particularly for CdCl₂ + 2-MeOE2, suggesting a protective redox-modulating effect of this metabolite. Resistant cells consistently displayed higher SOD1 activity and GST-pi expression, indicating enhanced adaptive responses to oxidative stress. Conclusions: Our study underscores the importance of concentration-dependent interactions between environmental Cd²⁺ and pathways regulated by 17β-estradiol and its metabolites, particularly in the context of cytotoxicity and redox imbalance relevant to breast cancer progression and therapy resistance. Full article

Introduction: Optimal systemic treatment for recurrent or advanced endometrial cancer (EC) remains uncertain, particularly in the second-line setting. While first-line chemotherapy with paclitaxel and carboplatin is widely used, its efficacy is limited. Recent evidence suggests that adding immune checkpoint inhibitors (ICIs) to chemotherapy (ChT) can improve progression-free survival (PFS). In addition, hormonal therapies (such as progestins and aromatase inhibitors), targeted therapies and ICIs used alone or in combination are emerging as potential treatment options. Objectives: Our objective was to systematically evaluate the efficacy and safety of systemic therapies beyond standard ChT for patients with recurrent or advanced EC, focusing on progression-free survival (PFS), overall survival (OS), and treatment-related adverse events (TRAEs). Methods: We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs), prospective studies, and retrospective studies up to June 2024 on PubMed, Embase, and CENTRAL. Studies evaluating systemic therapies—chemotherapy, hormonal therapy, targeted agents, and ICIs—in recurrent or advanced EC were included. Primary outcomes were PFS and OS; secondary outcomes included grade ≥ 3 treatment-related adverse events. Risk of bias was assessed using the Cochrane RoB 2 and MINORS tools, and GRADE was applied to evaluate the certainty of evidence. Results: Five RCTs evaluated the addition of ICI to conventional ChT. In mismatch repair-deficient (MMRd) patients, the addition of ICI significantly improved PFS and OS compared to the ChT-only group. In mismatch repair-deficient (MMRd) patients, the median PFS (mPFS) was 8.39 months in the ChT group and 22.73 months in the ICI group (HR: 0.34, p < 0.001). OS results were 26.48 and 41.36 months, respectively. In mismatch repair-proficient (MMRp) patients, mPFS was 9.4 months in the ChT group and 10.18 months at the ICI group (HR: 0.72, p = 0.002). OS was 27.37 and 27.79 months, respectively. We conducted several exploratory single-arm subgroup analyses and multiple individual patient data (IPD) meta-analyses across several clinically relevant subgroups, including patients treated with progestins, lenvatinib plus pembrolizumab, PI3K/AKT/mTOR inhibitor monotherapy, and PI3K/AKT/mTOR inhibitors in combination with aromatase inhibitors. Detailed descriptive analyses were performed for each subgroup. Conclusions: Combining chemotherapy with ICIs appears to show the most favorable survival outcomes, especially in MMRd tumors. Taking into account the methodological limitations inherent in the elaboration of lower-level evidence and IPD, hormonal and targeted therapies might be considered viable options, with efficacy and safety profiles dependent on tumor biology. Better stratification of the EC patient cohort is warranted. Full article

Background/Objectives: Metastatic hormone-sensitive prostate cancer (mHSPC) is a biologically heterogeneous disease in which treatment intensification with androgen receptor pathway inhibitors has significantly improved clinical outcomes. However, direct comparative evidence between abiraterone and enzalutamide remains limited. We aimed to evaluate radiographic progression-free survival (rPFS) in patients with mHSPC treated with first-line abiraterone or enzalutamide and to perform exploratory subgroup analyses according to baseline clinical and laboratory characteristics. Methods: This retrospective single-center study included patients with mHSPC who received first-line abiraterone or enzalutamide in combination with androgen deprivation therapy. Baseline demographic, clinical, and laboratory characteristics were collected retrospectively. The primary endpoint was rPFS. Survival was analyzed using the Kaplan–Meier method and compared using the log-rank test. Results: A total of 172 patients were included, of whom 84 received abiraterone and 88 received enzalutamide. The median follow-up duration was 24.7 months (95% CI 21.5–27.9). In the overall population, median rPFS was comparable between the abiraterone and enzalutamide groups (50 vs. 49 months, p = 0.21). However, enzalutamide was associated with significantly longer rPFS among patients aged <70 years (HR 0.25, 95% CI 0.07–0.89; p = 0.02), those with baseline hemoglobin ≥12 g/dL (HR 0.36, 95% CI 0.15–0.85; p = 0.01), and those with baseline ALP < 147 U/L (HR 0.43, 95% CI 0.19–0.98; p = 0.04). No significant differences were observed in other subgroups. Conclusions: rPFS was comparable between abiraterone and enzalutamide in the overall mHSPC population. However, enzalutamide was associated with longer rPFS in patients aged <70 years and in those with preserved hemoglobin and lower ALP levels. These findings suggest that baseline clinical and laboratory characteristics may influence treatment outcomes and should be prospectively validated. Full article

Introduction: Chronic kidney disease (CKD) involves a progressive loss of renal function and is characterized by chronic oxidative stress and kidney fibrosis. Tetrahydrocurcumin (THCu), a metabolite of curcumin, may possess antioxidant benefits in CKD. This study evaluated the transcriptomic changes and therapeutic potential of THCu against kidney damage and fibrosis in the 5/6 nephrectomy rat CKD model. Methods: Adult female Sprague–Dawley rats were randomized into CKD groups and three THCu doses were tested (100, 300 and 500 mg/kg). A liposomal formulation of THCu was given twice daily via oral gavage for 4 weeks. Serum creatinine and proteinuria were measured, and kidney fibrosis was assessed on histology. Kidney lysates were processed for total RNA sequencing to analyze differential gene expression in the experimental groups. The data were screened for outliers prior to ANOVA and correlation analyses. Results: In the untreated CKD group, serum creatinine and proteinuria were increased compared to control animals. Transcriptomic profiling revealed that untreated CKD animals exhibited marked upregulation across three key gene categories: immune cell activation, kidney injury and fibrosis, and inflammation and oxidative stress. THCu treatment mitigated these pathways by which there was downregulation of markers of immune cell activation as well as the kidney injury marker Kim1, while the fibrosis markers Col1a1 and Col3a1 were decreased to expression levels similar to non-CKD control animals. Furthermore, the highest dose of THCu at 500 mg/kg triggered a cellular detoxification and metabolic clearance response, with highly significant upregulation of Abcb11 and Gls2. Antioxidant benefit was evidenced by upregulation of Gpx1 in the high-dose THCu group compared to the untreated CKD group. Pathway enrichment analysis demonstrated that the high-dose THCu group restored key metabolic and signaling pathways disrupted in renal fibrosis, including small and organic solute metabolism, fatty acid oxidation, lipid biosynthesis, and peptide hormone response. Furthermore, the treatment upregulated essential anion and organic solute transport functions. Proteinuria was reduced with THCu therapy; however, serum creatinine and urine creatinine clearance were not significantly modified in comparison to untreated CKD rats. Conclusions: Oral THCu therapy demonstrated promising transcriptional changes in antioxidant and anti-fibrotic pathways in a rat CKD model. Confirmatory protein-level studies are needed to clarify benefits on kidney function. Full article