Therapeutics

Extensive evidence now confirms Lipoprotein(a) [Lp(a)] as a causal, independent risk factor for atherosclerotic cardiovascular disease. Elevated Lp(a) levels are detected in approximately 20% of the global population, positioning it as a major contributor to residual cardiovascular risk. Circulating Lp(a) levels are determined predominantly by genetic factors, so they are largely unresponsive to lifestyle modifications or conventional lipid-lowering therapies. Therefore, multiple international guidelines now endorse a one-time, lifetime measurement of Lp(a), as lowering Lp(a) concentrations is expected to have a positive impact on the reduction of cardiovascular risk. Currently, the therapeutic landscape of Lp(a) lowering drugs is rapidly evolving. Some RNA-based therapies (antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs)) have been demonstrated to reduce plasma Lp(a) concentrations by up to 98% in early-phase clinical trials. The efficacy and safety of these compounds are currently being evaluated in large-scale cardiovascular outcome trials. The results of these studies will be critical in validating the “Lp(a) hypothesis”: specific reduction of Lp(a) levels can lead to a measurable decrease in cardiovascular events. The purpose of this narrative review is to examine and discuss the available evidence on the role of Lp(a) as a risk factor and pharmacological target to provide a practical tool for decision-making in clinical practice. Full article

Background/Objectives: Children at cardiovascular risk require effective non-pharmacological strategies to improve cardiometabolic health. This study aimed to evaluate the effectiveness of physical activity and lifestyle-based interventions on blood pressure and related cardiovascular risk markers in children and adolescents. Materials and Methods: A systematic review and meta-analysis were conducted in accordance with PRISMA guidelines and registered in PROSPERO (CRD42025644256). Searches were performed in MEDLINE (PubMed), SPORTDiscus (EBSCO), and the Cochrane Library from January 2015 to March 2025. Methodological quality and risk of bias were evaluated using the PEDro scale, RoB 2.0, and GRADE. Results: Twenty-nine studies were included, showing overall high methodological quality. Pooled analyses showed a statistically significant reduction in systolic blood pressure (SMD = −0.35; 95% CI: −0.40 to −0.31; p < 0.00001, I² = 83%). Diastolic blood pressure also showed a small but statistically significant reduction (SMD = −0.06; 95% CI: −0.11 to −0.01; p = 0.01; I² = 93%), equivalent to an estimated decrease of about 1 mmHg. Fasting insulin levels were significantly reduced (SMD = −0.92; 95% CI: −1.27 to −0.56; p < 0.00001), suggesting improvements in metabolic regulation despite considerable heterogeneity (I² = 95%). In contrast, pooled effects for body fat percentage (%) (SMD = 0.11; 95% CI: −0.10 to 0.32; p = 0.31) and BMI z-score (standardized units) (SMD = 0.13; 95% CI: −0.04 to 0.31; p = 0.14) were not statistically significant, with very high between-study variability. Conclusions: Multicomponent interventions integrating physical activity with lifestyle modification appear effective in reducing systolic and diastolic blood pressure and improving insulin sensitivity in children and adolescents at elevated cardiovascular risk. Although the magnitude of blood pressure reductions is modest, even small decreases at the population level may contribute to meaningful long-term cardiovascular risk reductions. Full article

Cryptococcal meningitis occurs in 62% of persons with HIV-associated meningitis, making Cryptococcus an important cause of meningitis among adults with advanced HIV disease in regions with elevated prevalence of HIV. Despite efforts to advance treatment, the in-hospital death rate of 19% remains unprecedentedly high. Aggregate published clinical trial data evaluating cryptococcosis treatment with survival as the primary endpoint show a significant reduction in the proportion of survivors from diagnosis to 88.5% at 2 weeks of treatment and further to 74% survival at 10 weeks of follow-up (p = 0.001). Disease complications concomitant with unveiling symptoms and reoccurrence of fungal infections, deferment in treatment, and high prevalence of other comorbidities increase the risk of individuals succumbing to cryptococcal meningitis. Among clinical trials of cryptococcal meningitis, the World Health Organization-recommended standard of care was used to randomize participants to the control trial arm. The proportion of participants surviving in the trial was not statistically different between trial randomization arms. In summary, high in-hospital death rates and continued participants’ deterioration post-hospital discharge are challenges for evidence-based new therapies seeking to improve outcomes. Full article

Background/Objectives: Pyoderma gangrenosum (PG) is a rapidly progressive, ulcerating condition that can cause large, painful lesions when uncontrolled. There is currently no standard of care treatment for severe PG ulcers refractory to systemic treatment. The present study aims to characterize the outcomes of placental allografts in treating severe PG lesions. Methods: A single institution retrospective chart review was conducted at the University of South Florida affiliated sites examining PG patients that received placental allograft treatment. Results: The review returned five patients with clinically diagnosed or biopsy-proven PG treated with placental allograft. In all five patients, application of placental allograft resulted in varying degrees of short-term (<1 month) improvement. Near-complete resolution was observed in one patient. Out of the 20 total allografts placed between the 5 patients, only one had an adverse event of infection within one week of placement. Grafts were otherwise very well tolerated by all patients. Conclusions: Placental allografts show promising adjunctive therapeutic potential for severe PG lesions with preliminary findings showing good viability and safety profiles. Future prospective controlled studies should be performed to further examine the viability of this adjunctive treatment in this disease. Full article

Introduction: Radioresistance in prostate cancer (PCa) poses a major therapeutic challenge. Galectin-3 (Gal-3) is overexpressed in aggressive PCa and may contribute to resistance mechanisms. This study evaluated the role of Gal-3 in radioresistance and assessed the effect of its pharmacological inhibition using GB1107. Methods: Parental (22RV1-P) and radioresistant (22RV1-RR) PCa cell lines were treated with GB1107. Western blotting assessed Gal-3 and Protein Phosphatase 1 alpha (PP1α) expression. Cell viability (PrestoBlue™), migration (wound assay), and clonogenic survival post-irradiation were evaluated. Statistical significance was set at p < 0.05. Results: Gal-3 was significantly upregulated in 22RV1-RR cells (p = 0.0237). GB1107 reduced viability and impaired migration in both cell lines. Radiosensitisation was observed in 22RV1-P cells (p < 0.0001) but was not significant in 22RV1-RR cells (p = 0.1258). A non-significant increase in PP1α expression was detected in RR cells. Conclusion: Gal-3 contributes to radioresistance. Further studies are needed to clarify the role of PP1α and optimise Gal-3-targeted strategies. Full article

Artificial Intelligence (AI) and Precision Medicine are increasingly influencing pediatric pharmacotherapy, where age-dependent pharmacokinetic variability demands highly individualized therapeutic strategies. This review examines current applications of AI in pediatric precision medicine and evaluates their clinical relevance and translational challenges. Recent evidence shows substantial progress across multiple domains. In pharmacogenomics, predictive models have reached R² = 0.95 for drug exposure. Tools for adverse drug reaction detection report sensitivities of 81.5% and specificities of 79.5%. Clinical decision support systems for pediatric epilepsy have achieved diagnostic accuracies of 93.4%. Real-world implementations have been associated with a 75% reduction in prescription distribution errors and a 65% improvement in adverse drug reaction detection. Despite these advances, clinical translation remains limited: only 0.38% of pediatric AI models progress to testing in real patients, and 77% of published studies carry a high risk of bias. These gaps highlight the need for rigorous validation, improved data quality, and careful consideration of ethical and algorithmic constraints. Overall, AI has the potential to shift pediatric pharmacotherapy from empirically driven decisions toward predictive, precision-based approaches. Achieving this goal will require well-designed pediatric studies and sustained interdisciplinary collaboration to ensure safe and effective integration into clinical practice. Full article

Background: The signal peptide-CUB-EGF-like domain-containing protein 3 (SCUBE3) is a secretory protein that plays a role in cancer, cardiovascular, and immune disorders. SCUBE1, SCUBE2, and SCUBE3 belong to the SCUBE family. They contain multiple copies of EGF-like repeats at the amino acid terminal, a spacer region, three cysteine-rich motifs, and a CUB domain at the carboxyl terminus. The SCUBE family members are multifunctional proteins that act primarily as extracellular ligands or co-receptors in various cells. Methods: In this study, we examined the expression pattern and role of SCUBE3 in various cancers, as well as other diseases such as cardiovascular disease and immune disorders, and its impact on growth and development. Results: SCUBE3 expression is upregulated and secreted by the cells of lung cancer, hepatocellular carcinoma (HCC), melanoma, osteosarcoma, ovarian cancer, glioma, and breast cancer. Extracellular SCUBE3 protein often binds to TGFβRII or acts as a co-receptor for TGFβ and BMP2/BMP4 in regulating cellular signaling. Through the TGFβRII signaling, SCUBE3 activities promote tumor growth, metastasis, invasion, angiogenesis, and poor clinical outcomes. Conversely, in renal cell carcinoma, SCUBE3 expression suppresses growth. Altered SCUBE3 activity is associated with cardiovascular diseases, immune disorders, and hair growth. Conclusions: The review presents mechanistic evidence that SCUBE3 plays a crucial regulatory role in multiple cancers and other diseases. The evidence suggests the SCUBE3 protein could serve as a potential molecular target for various diseases and highlights its usefulness as a minimally invasive diagnostic marker, as it is a secreted protein. Full article

Background: Hyponatremia (serum sodium levels below 135 mEq/L) is the most prevalent electrolyte imbalance, with the syndrome of inappropriate antidiuresis (SIAD) being the most common cause among inpatients. Fluid restriction is the primary treatment for SIAD, yet its efficacy is inconsistent. A novel therapeutic approach involves the use of oral vaptans, such as tolvaptan (TLV), which are non-peptide antagonists of arginine vasopressin receptors. The recommended daily dose of TLV is 15 mg; however, the risk of overcorrection and osmotic demyelination syndrome must be considered. Methods: Consequently, a more cautious approach involving a 7.5 mg dose of TLV was studied in SIAD patients to determine its safety and efficacy compared with a 15 mg dose. Results: The findings of our investigation show that the results obtained from the two doses are highly similar. However, it is important to note that the risk of overcorrection was lower in the 7.5 mg TLV group than in the 15 mg group. Furthermore, a more gradual increase in serum Na was observed in the 7.5 mg group than in the 15 mg group after the most critical first 24 h. Conclusions: TLV therapy can be initiated with a 7.5 mg dose, with serum sodium levels monitored at 12 and 24 h to confirm or adjust the TLV dose as required. Full article

Background/Objectives: Pes planus is characterized by loss of medial longitudinal foot arch, resulting potentially in dysfunction in balance. Chronic ankle instability (CAI) is related to sensorimotor control deficits. Both of these two musculoskeletal disorders have a diminishing effect on joint proprioception. The present study examined the impact of flatfoot on balance in individuals with CAI. Methods: A total of 28 students (15 men, 13 women; 18–23 years, M = 20.46, SD = 1.07) were assigned to CAI with pes planus (n = 15) or CAI only (n = 13). Balance was assessed using the Y-balance test (YBT) and modified star excursion balance test (mSEBT) in three directions (anterior, posteromedial, and posterolateral), alongside the Cumberland ankle instability tool (CAIT). Group differences were analyzed with independent t tests or Mann–Whitney U tests (α = 0.05). Results: The findings of the study did not show statistically significant differences between the two groups in the balance variable [mSEBT/anterior left foot (t = 0.239, p = 0.865); mSEBT/posteromedial left foot (t = −0.048, p = 0.562); mSEBT/posterolateral left foot (t = 0.164, p = 0.258); mSEBT/anterior right foot (t = −0.433, p = 0.748); mSEBT/posteromedial right foot (t = 0.745, p = 0.606); mSEBT/posterolateral right foot (t = 0.263, p = 0.680); YBT/anterior left foot (U = 96.00, p = 0.93); YBT/posteromedial left foot (U = 94.50, p = 0.87); YBT/posterolateral left foot (U = 96.00, p = 0.93); YBT/anterior right foot (U = 95.50, p = 0.92); YBT/posterolateral right foot (U = 82.50, p = 0.45)]. However, a trend towards significance was found as patients with flatfeet had a weaker performance in balance tests [posteromedial direction of the YBT for the right foot (U = 70.00, p = 0.12)]. Conclusions: Although pes planus did not seem to affect the balance ability of individuals with CAI, future studies should confirm the relationship of pes planus and CAI with a larger group, including variables such as ankle range of motion, muscle strength, and functional activity level. A better understanding of the above relationship may lead to more precise diagnostic processes and more efficient therapies in CAI. Full article

Alcohol-associated liver disease, particularly severe alcoholic-associated hepatitis (AH), remains a major cause of morbidity and mortality worldwide. Conventional treatments, including corticosteroids, offer limited short-term benefit and are contraindicated in many patients, necessitating exploration of alternative therapies. Fecal microbiota transplant (FMT) has emerged as a novel therapeutic intervention, targeting the gut–liver axis that is disrupted in AH. This review synthesizes the current literature on FMT in the management of alcohol-induced liver injury, examining its pathophysiological basis, clinical efficacy, and implementation challenges. Dysbiosis and increased gut permeability in patients with alcohol use disorder contribute to systemic endotoxemia and hepatic inflammation. FMT aims to restore microbiota diversity and gut barrier integrity, mitigating the progression of liver injury. Some clinical trials have demonstrated encouraging survival benefits and modulation of gut microbiota composition in patients with severe AH. These studies report improved one-year survival rates and reductions in pathogenic bacterial taxa following FMT. However, the field remains nascent, with unresolved questions regarding optimal donor selection, sample preparation, administration routes, and long-term safety. Despite limited large-scale randomized data, FMT shows potential as an adjunct or alternative to existing therapies. Continued research is needed to establish standardized protocols and fully elucidate its role in the treatment algorithm for AH. Given the high mortality associated with untreated severe AH and limitations of current therapies, FMT represents a promising frontier in the management of alcohol-associated liver disease. Full article

Background: Combination therapy for Enterococcus faecalis was established in the 1940s due to high rates of treatment failure, especially for infective endocarditis (IE). However, during this period antimicrobials were limited, optimal dosing was unknown, and development of resistance was rapid. Today, nearly 80 years later, combination therapy is still the standard practice for IE caused by E. faecalis despite improvements in antimicrobial availability, activity, and evidence-based, optimized antimicrobial dosing. These treatment decisions are guided by in vitro synergy principles and are frequently extrapolated to E. faecalis bloodstream infections (BSI) without IE. The paucity of clinical data to support this practice, paired with the known risks from unnecessary antibiotic exposure, makes further research and clinical guidance necessary. Methods: This single-center retrospective observational study of hospitalized adult patients with E. faecalis BSI treated with combination therapy aimed to describe treatment approaches and outcome data. Results: Between 1 January 2017, and 30 September 2024, 358 patients were screened, and 54 met study inclusion criteria. IE was present in 53.7% of patients, and 25.9% met the composite outcome (30-day mortality, 60-day hospital readmission, and/or 60-day recurrence). Adverse events were noted in 5.6% of patients. Conclusions: Observational data from this review supports the hypothesis that guideline recommendations for the use of combination therapy in E. faecalis IE are occasionally extrapolated to patients without IE. Given the in vitro and dated observational data used as the basis for these recommendations and the risks associated with unnecessary antibiotic exposure, more extensive, prospective, interventional studies are needed to address this dogmatic practice surrounding a high-morbidity, high-mortality disease state. Full article

Background/Objectives: Our objective was to describe the safety and efficacy of enteral droxidopa, a norepinephrine prodrug, for intravenous (IV) vasopressor weaning in intensive care unit (ICU) patients. Methods: This was a single-center, retrospective descriptive study of adult ICU patients. Patients who received ≥ 4 consecutive doses of droxidopa for IV vasopressor weaning were included. The cessation of the IV vasopressor without re-initiation within 72 h of droxidopa initiation was the primary outcome. The adverse events assessed included hypotension, hypertension, and arrhythmias. Results: Forty-six patients were included, with a median age of 61. Forty-two patients (91%) were on midodrine at the time of droxidopa initiation. The median daily midodrine dose was 80 mg. The median time from ICU admission to droxidopa initiation was 17 days. Patients were on a median of one IV vasopressor at the time of droxidopa initiation, with norepinephrine as the most common agent (50%). The median initial daily droxidopa dose was 300 mg, with a median maximum daily dose of 900 mg. Vasopressor support was discontinued within 72 h of droxidopa initiation in 46% of patients, with a median time to IV vasopressor cessation of 3.3 days. There were no incidences of hypotension, hypertension, arrhythmias, or ICU readmissions related to droxidopa. Droxidopa was continued upon discharge in 29% of patients. Conclusions: Droxidopa may be a safe and effective option to facilitate the weaning of IV vasopressor support in patients who are refractory or intolerant to midodrine. Larger prospective studies are needed to confirm these findings. Full article

Background: Psoriasis has a huge impact on a patient’s life. Treatment dissatisfaction and non-adherence are common among patients with psoriasis, partly due to discordance between individual preferences and recommended treatments. The modern strategy for psoriasis should be focused on human-centric treatment that recognizes the needs and preferences of patients with a goal for safe, effective, quality and acceptable health services for a lifetime. The aim of this analysis was to capture patients’ preferences with moderate-to-severe psoriasis regarding various treatment attributes. Methods: A specialized questionnaire containing four attributes with three levels, each, was used, followed by an orthogonal plan based on conjoint analysis. Nine combinations of therapeutic scenarios were produced as a result, to investigate participants’ preferences. Respondents were asked to rank alternatives from best to worst. Results: The risk of developing pneumonia or other serious infections within a decade seems to be higher in patients with an implied assigned value of 37. The second attribute was the type and frequency of the administration with a value of 27, followed by the treatment effectiveness with great improvement of body surface with a value of 25. The lowest utility (11) was the sustainability of early remission of psoriasis. Conclusions: Psoriasis patients want safe, effective and easy to administer treatments. Full article

Hematopoietic stem cell (HSC) therapy remains essential in treating blood disorders, autoimmune diseases, neurodegenerative conditions, and cancers. Despite its potential, challenges arise from the inherent heterogeneity of HSCs and the complexity of their regulatory niche. Recent advancements in single-cell RNA sequencing and chromatin accessibility sequencing have provided deeper insights into HSC markers and chromatin dynamics, highlighting the intricate balance between intrinsic and extrinsic regulatory mechanisms. Zebrafish models have emerged as valuable tools in HSC research, particularly through live imaging and cellular barcoding techniques. These models have allowed us to describe critical interactions between HSCs and embryonic macrophages, involving reactive oxygen species and calreticulin signaling. These are essential for ensuring HSC quality and proper differentiation, with implications for improving HSC transplant outcomes. Furthermore, the review examines clonal hematopoiesis, with a focus on mutations in epigenetic regulators such as DNMT3A, TET2, and ASXL1, which elevate the risk of myelodysplastic syndromes and acute myeloid leukemia. Emerging technologies, including in vivo cellular barcoding and CRISPR-Cas9 gene editing, are being investigated to enhance clonal diversity and target specific mutations, offering potential strategies to mitigate these risks. Additionally, macrophages play a pivotal role in maintaining HSC clonality and ensuring niche localization. Interactions mediated by factors such as VCAM-1 and CXCL12/CXCR4 signaling are crucial for HSC homing and the stress response, opening new therapeutic avenues for enhancing HSC transplantation success and addressing clonal hematopoiesis. This review synthesizes findings from zebrafish models, cutting-edge sequencing technologies, and novel therapeutic strategies, offering a comprehensive framework for advancing HSC biology and improving clinical outcomes in stem cell therapy and the treatment of hematologic diseases. Full article

Background/Objectives: Cytomegalovirus (CMV) infection is a frequent complication after lung transplantation, especially in high-risk donor-positive/recipient-negative (D+/R−) patients. CMV-specific hyperimmunoglobulin (CMV-HIG), administered either with antivirals or as monotherapy, may be beneficial for preventing or treating CMV infection in selected clinical scenarios. This study evaluated CMV-HIG indications and their impact on clinical outcomes in our lung transplant unit. Methods: We retrospectively analyzed adult lung transplant recipients (2010–2023) who received ≥2 doses of CMV-HIG for universal prophylaxis, monotherapy prophylaxis, preemptive therapy, or treatment of invasive disease. Results: CMV-HIG was administered to 204 out of 336 recipients (61%). CMV-HIG was well tolerated, with no treatment-related adverse events. Indications were preemptive therapy (63%), universal prophylaxis (24%), monotherapy prophylaxis (7%), and treatment of invasive disease (6%). CMV-HIG was well tolerated, with no treatment-related adverse events. No patients developed invasive disease during combination prophylaxis or preemptive treatment. The combination treatment of patients with invasive disease was also effective, and no cases of VGC resistance were detected. CMV-HIG monoprophylaxis has allowed us to delay or prevent viral replication in recipients who developed VGC side effects. Rates of acute rejection, Chronic Lung Allograft Dysfunction (CLAD), and overall survival were similar across CMV risk groups. Conclusions: Our results showed that the combined use of CMV-HIG and antiviral agents is effective in preventing CMV infection and disease in high-risk lung transplant recipients. This combination is also useful in treating invasive disease and preventing VGC resistance. Additionally, CMV-HIG monoprohylaxis can delay or prevent viral replication in recipients experiencing VGC-related side effects. These findings support the use of CMV-HIG in selected clinical settings, although prospective studies are needed to define its potential benefits within the current therapeutic armamentarium. Full article

Background/Objectives: Biochemical recurrence (BCR) occurs in 15–40% of men within five years of radical prostatectomy (RP), presenting a major challenge for long-term disease control. While salvage radiotherapy (SRT) and androgen deprivation therapy (ADT) are established post-RP interventions, the optimal integration of ADT with SRT—regarding timing, duration, and patient selection—remains unclear. We aimed to synthesize current clinical evidence on the efficacy and safety of combining ADT with SRT in patients experiencing BCR after RP. Methods: A narrative review was conducted, encompassing retrospective cohort studies, prospective randomized controlled trials (notably RTOG 9601, GETUG-AFU 16, RADICALS-HD, and SPPORT), and meta-analyses. Studies were selected based on relevance to combined ADT + SRT versus SRT alone, with outcomes of interest including biochemical progression-free survival (bPFS), metastasis-free survival (MFS), and overall survival (OS). Trial characteristics, ADT duration (short-term [4–6 months] versus long-term [≥24 months]), radiation scheme, and prostate specific antigen (PSA) thresholds at SRT initiation were extracted and compared. Results: The combination of ADT and SRT represents a promising strategy for the treatment of prostate cancer with BCR after RP. Current evidence supports its benefit in terms of disease control and survival, particularly in high-risk patients. Conclusions: Differences in inclusion criteria, ADT duration, and the heterogeneous quality of the available studies limit the formulation of universal recommendations. Well-designed prospective trials are needed to optimize therapeutic approaches and personalize treatment based on each patient’s risk profile. Full article

Background: The outgrowth of castration-resistant prostate cancer (CRPC) dictates patient morbidity and mortality. Recurrence of prostate cancer (PC) following androgen-deprivation therapy (ADT) often occurs due to constitutively active androgen receptor (AR) splice variants (AR-Vs), primarily AR-V7. Therefore, safe and effective therapies enabling the suppression of both full-length AR (AR-FL) and AR-Vs are urgently needed. The natural compound dimethyl sulfoxide (DMSO) has negligible cytotoxicity at concentrations below 5% and has anticancer potential. DMSO has been broadly used in biomedical research as a solvent for pharmaceuticals, as a cryoprotectant for cells, and as a topical treatment to suppress pain and inflammation. We investigated the effect of low-dose DMSO on AR expression, cell viability, and metastatic ability in PC cell lines expressing both AR-FL and AR-V7 (e.g., 22Rv1) and those expressing only AR-FL (e.g., C4-2B). Methods: MTT cell viability assays were performed to measure DMSO-induced cytotoxicity. Wound-healing assays were conducted to monitor the effect of DMSO on the migratory phenotype of cancer cells. Western blot analyses were performed to study the efficacy of DMSO in suppressing the protein levels of AR-FL and AR-V7, and expression of heterogeneous nuclear ribonucleoprotein H1 (hnRNPH1) was measured as a possible mechanism. Results: At concentrations of 0.1–1% (v/v), DMSO treatment showed minimal cytotoxicity, whereas the highest concentration used (2.5%) showed approximately 20% cytotoxicity at 96 h. Interestingly, however, DMSO treatment at concentrations of 1.0 and 2.5% significantly inhibited the migration of PC cells. Treatment with DMSO led to a dose-dependent inhibition of both AR-FL and AR-V7. Notably, in 22Rv1 cells, DMSO potently downregulated the expression of hnRNPH1, a splicing factor often associated with AR expression and signaling. Conclusions: Our findings suggest that low concentrations of DMSO may have potential as an effective anticancer agent, both at the initial and later stages when PC cells become castration resistant. Full article

Background/Objectives: Gender-affirming surgery (GAS) is associated with improved mental health outcomes in transgender and gender-diverse (TGD) individuals. However, TGD populations experience disproportionately high rates of substance use disorders (SUDs), which are established risk factors for surgical complications. Despite this, the relationship between preoperative SUDs and postoperative outcomes following GAS has not been studied. Our objective was to evaluate how specific SUD subtypes, including tobacco, alcohol, and cannabis, impact short- and medium-term postoperative complications following GAS. Methods: A retrospective cohort study was conducted using the TriNetX Research Network, which includes de-identified electronic health records from over 100 million U.S. patients. Adults with documented gender dysphoria who underwent GAS between April 2015 and April 2025 were included. Patients were divided into four groups: no SUD, tobacco use, alcohol use, and cannabis use. Propensity score matching was used to control for demographic variables. Postoperative complications were assessed at 30 days and 6 months. Results: Alcohol use was significantly associated with increased rates of delayed wound healing, wound dehiscence, gastrointestinal symptoms, and postoperative pain at both 30 days and 6 months. Cannabis use was linked to higher rates of wound dehiscence, infections, GI symptoms, and pain. Tobacco use showed the broadest impact, significantly associated with nearly all complications measured except pain at 30 days. These associations persisted at six months. Conclusions: This is the first study to quantify the relationship between substance use and GAS outcomes. Preoperative use of tobacco, alcohol, and cannabis was independently associated with increased postoperative complications. These findings underscore the need for systematic preoperative screening and the development of SUD-specific perioperative care pathways to improve outcomes and advance equity in surgical care for TGD patients. Full article