Abstract Purpose Immune checkpoint inhibitors (ICIs) are the preferred treatment for advanced hepatocellular carcinoma (HCC). However, most patients do not respond to initial immunotherapy alone, even when combined with other therapies. Our study aimed to profile ICI-based therapies for HCC patients in real-world clinical practice and to identify factors associated with survival and treatment efficacy. Methods A retrospective cohort study was conducted to describe ICI-based therapies for HCC patients at our center, including combination modalities, effectiveness, and safety. Pre- and post-treatment indicators were collected to explore factors related to progression-free survival (PFS) and treatment efficacy in these patients. Results All 110 patients received therapy based on immune checkpoint inhibitors (ICIs) using three strategies, with the majority (60.9%) undergoing triple combination therapy. The overall progression-free survival (PFS) was 7.0 months, and the objective response rate (ORR) was 26.4%. Analysis of PFS identified several independent risk factors: a history of hepatitis B virus (HBV) infection (hazard ratio [HR] = 1.78), a platelet-to-lymphocyte ratio (PLR) greater than 276.9 (HR = 2.19), and an international normalized ratio (INR) greater than 1.2 (HR = 3.49). Conversely, the use of PD-1 inhibitors was associated with a favorable outcome (HR = 0.44). The combination of a history of HBV infection with HBeAg positivity and TNM stage (III + IV) effectively distinguished responders from non-responders. Additionally, neutrophil count and the neutrophil-to-lymphocyte ratio (NLR) were significantly elevated in non-responders and exhibited dynamic changes during treatment. Conclusion In HCC clinical practice, ICI-based systemic therapies are both effective and safe. Patient characteristics can serve as reliable predictors of progression-free survival (PFS) and treatment efficacy. Importantly, neutrophil count and the neutrophil-to-lymphocyte ratio (NLR) may also be used as potential biomarkers for efficacy conversion, rather than just as predictors.

This study assessed the efficacy and tolerability of the oral prostacyclin receptor agonist selexipag as part of sequential triple combination therapy in patients with pulmonary arterial hypertension (PAH). The study retrospectively analyzed 127 of 1160 PAH patients from a single-center registry who received sequential triple therapy including selexipag. Clinical, echocardiographic, and hemodynamic variables and multiparametric risk scores (MRS) were evaluated to assess changes in risk and outcomes. The mean age was 43.2 ± 16.4 years, and 84.3% were female. Prior to selexipag initiation, Comparative Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension 2.0 risk strata were: 15% first, 31.5% second, 44.1% third, and 9.4% fourth; European Society of Cardiology/European Respiratory Society low-, intermediate-, and high-risk rates were 20.5%, 61.4%, and 18.1%, respectively. Mean REVEAL Lite 2.0 score was 6.3 ± 2.7. Maximal selexipag dosing reached 1600 μg BID in 18.1% of patients, while 64.6% remained at ≤1000 μg BID. Patients were grouped into low-, intermediate-, and high-dose cohorts. Median follow-up was 727.5 days (interquartile range (IQR) 224-985). Selexipag was discontinued in 15% of patients. Across dosing cohorts, initial improvements in functional class, 6-minute walk distance, right ventricular and pulmonary echocardiographic parameters, and MRSs during the first year attenuated thereafter, except for N-terminal pro-brain natriuretic peptide and Tricuspid annular plane systolic excursion/pulmonary arterial systolic pressure ratio. Lower baseline REVEAL Lite 2.0 score predicted low-risk status at final assessment (P = .017). Three-year survival was 72.5%, 85.7%, and 75.1% in low-, medium-, and high-dose cohorts (P > .05). Mortality was independently predicted by baseline Swedish PAH Registry, REVEAL 2.0, REVEAL Lite 2.0, and REVEAL Echo scores. Earlier escalation to triple therapy with selexipag may improve outcomes. Baseline risk-but not achieved selexipag dose-was associated with survival. A possible decline in treatment effect after 1 year warrants further investigation.

BackgroundCatheter-related or central line-associated bloodstream infection (CRBSI/CLABSI) causes substantial morbidity and mortality. Managing CRBSI/CLABSI often involves removing the infected central venous catheter (CVC) and inserting a new one at a different vascular site. Currently, no adjunct antimicrobial lock therapy (in combination with systemic antibiotics) has been FDA-approved and is urgently needed. Our study evaluated a novel triple combination antimicrobial therapy (Mino Lok (MLT)) containing minocycline, EDTA, and ethanol. MLT has shown broad-spectrum in-vitro activity and positive results in a Phase 2 trial.MethodsThis international, multicenter, superiority trial was conducted at 34 sites. Cancer, hemodialysis (HD), or other patients requiring a long-term CVC (LTCVC), aged ≥ 12 years, with CLABSI/CRBSI, were enrolled and randomized in a 1:1 ratio to receive either MLT or site-specific standard of care (SOC) antimicrobial lock for 2 hours/day for 7 days. The primary endpoint was median time to catheter failure (defined as mortality, catheter removal due to inability to administer lock or infectious-related reasons, worsening signs/symptoms, persistent or recurrent bloodstream infection, or deep-seated infection).ResultsFrom February 2018 to February 2024, 241 subjects were enrolled and randomized with 228 receiving study drug. A significant difference in median time to catheter failure in intent-to-treat (ITT) and modified ITT (MITT) populations (p≤ 0.0006) was observed (Figures 1 & 2). The CVC was successfully retained in 57% of patients in MLT vs 38% in SOC (p=0.0025). Clinical and microbiological failure related to the catheter or CLABSI were significantly higher in SOC (p=0.0058 and p=0.012, respectively) (Table 1). Adverse events (AEs), serious AEs (SAEs) and all-cause mortality were comparable for the two groups. There were no drug-related SAEs.ConclusionThis phase 3 pivotal study demonstrated MLT to be highly effective and superior to SOC antimicrobial locks in salvaging LTCVCs associated with CRBSI/CLABSI in cancer, HD and other patients requiring LTCVC. MLT has broad-spectrum activity, was well-tolerated, and was not associated with drug-related SAEs. MLT may satisfy an urgent unmet need in the management of CRBSIs/CLABSI.DisclosuresAnne-Marie Chaftari, MD, Citius Pharmaceuticals, Inc., Cranford, New Jersey, USA: Grant/Research Support Vinay Rathore, MD, Citius Pharmaceuticals, Inc. 11 Commerce Drive, First Floor Cranford: Grant/Research Support Paul P. Cook, MD, Gilead: Grant/Research Support|Janssen: Grant/Research Support|Pfizer: Grant/Research Support Onix Cantres-Fonseca, MD, Citius Pharmaceuticals, Inc.: Grant/Research Support Mayur Ramesh, MD, Citius Pharmaceuticals, Inc.: Grant/Research Support Mark E. Rupp, MD, Armata: Advisor/Consultant|Citius Pharmaceuticals, Inc.: Advisor/Consultant|Magnolia: Grant/Research Support|Teleflex: Advisor/Consultant Leonard Mermel, DO, Citius Pharma: Advisor/Consultant|CorMedix Pharma: Advisor/Consultant|Destiny Pharma: Board Member|Lightline Medical: Advisor/Consultant|Pristine Access Technology: Advisor/Consultant|Pristine Access Technology: Stocks/Bonds (Private Company) Alan Lader, PhD, Citius Pharmaceuticals, Inc.: Senior Vice-President/employee Issam I. Raad, Distinguished Professor, Citius Pharmaceuticals, Inc. (Grant/Research Support): Advisor/Consultant|Citius Pharmaceuticals, Inc. (Grant/Research Support): Grant/Research Support|Citius Pharmaceuticals, Inc. (Grant/Research Support): Patent|Citius Pharmaceuticals, Inc. (Grant/Research Support): Ownership Interest|Citius Pharmaceuticals, Inc. (Grant/Research Support): Stocks/Bonds (Public Company)|Spectrum Vascular: Patent|Spectrum Vascular: Ownership Interest

Dual-Targeting CD133/PD-L1 CAR-T plus αPD-1 Overcomes Immunosuppressive Microenvironment and Enhanced by Radiation Pre-conditioning through Induction of a Tissue-resident Memory Phenotype.

The efficacy of a triple combination of rabbit anti-human thymocyte immunoglobulin (rATG), ciclosporin and eltrombopag (EPAG) was prospectively evaluated in patients with severe or transfusion-dependent non-severe aplastic anaemia (SAA) across 29 institutions in Japan. Sixty patients were enrolled, of whom 48 had SAA. The primary end-point, the haematological overall response rate at 12 weeks, was 52.6% (95% confidence interval, 39.0%-66.0%), increasing to 67.9% at 26 weeks. The most frequent grade 3/4 adverse event was febrile neutropenia (20.0%). One elderly patient with severe neutropenia died of sepsis. Progression to myelodysplastic syndrome (MDS) or acute myeloid leukaemia (AML) was observed in one patient each. There was no association between the haematological response and high thrombopoietin levels, presence of paroxysmal nocturnal haemoglobinuria-type cells or Human Leukocyte Antigen (HLA)class I allele-lacking cells. Five patients (8.5%) had chromosomal abnormalities at baseline with no subsequent progression to MDS or AML. By 26 weeks, chromosomal abnormalities had emerged or expanded in eight patients (17.4%), although abnormalities of chromosome 7 were not observed within 52 weeks. These results suggest that triple therapy with rATG may be as effective as that with horse anti-human thymocyte immunoglobulin. Notably, the addition of EPAG did not induce chromosomal abnormalities associated with poor prognosis.

Ultraprecision Therapy for Type 1 vs Type 2 CALR+ MPN by Dual Epitope Targeting that Restores Ruxolitinib Sensitivity.

Evidence of a therapeutic window for TNF-α inhibitor and IVIG benefits in SJS/TEN treatment - A multicenter 6-year retrospective study.

Rational design of 1H-pyrrole-2-carboxylic acid inhibitors of NDM-1 metallo-β-lactamase restoring β-lactam efficacy against resistant Enterobacterales.

Mango seed kernel extract (MSKE) and its phytochemical compositions were investigated for their anticancer activities and synergistic effects with doxorubicin (DOX) against hepatocellular carcinoma (HCC) in both 2D and 3D culture models. Molecular docking studies were conducted to elucidate the mechanisms of DOX, MSKE, and major phytochemical components against overexpressed HCC-related proteins. Co-delivery of DOX and MSKE demonstrated significant synergistic anticancer activity in both models. A sequential nanotheranostic platform (SNP), consisting of MSKE encapsulated aminated hollow mesoporous silica nanoparticles capped with graphene quantum dots (GQD-MSKE-NH2HMSNs) and DOX encapsulated HMSNs (DOX-HMSNs), was synthesized for HCC treatment. GQD conjugation allowed real-time cellular tracking and photothermal therapy (PTT). The SNP exhibited particle sizes of 96.12 ± 5.12 nm for GQD-MSKE-NH2HMSNs and 94.99 ± 6.30 nm for DOX-HMSNs, both with positive surface charges. Encapsulation efficiency (%EE) and loading capacity (%LC) of GQD-MSKE-NH2HMSNs were 95.50 ± 0.20% and 46.72 ± 1.14%, respectively, while DOX-HMSNs achieved 96.42 ± 2.48 %EE and 29.0 ± 0.70 %LC. GQD-MSKE-NH2HMSNs provided PTT and disrupted the tumor microenvironment, collagen type 1, thereby enhancing the penetration of GQD-MSKE-NH2HMSNs in 3D-HCC spheroids. In parallel, DOX-HMSNs exhibited a pH-responsive drug release behavior, allowing controlled DOX delivery in the acidic tumor area. Therefore, the SNP demonstrated significantly higher anticancer efficacy than the combination of MSKE and DOX at equivalent concentrations and provided the synergistic effect of the triple combination therapy (herbal adjuvant, PTT and chemotherapy) against HCC.

Strategies for the identification of people with cystic fibrosis responsive to CFTR modulator triple combinations.

Objective: To evaluate the effects of the measles virus (MV) in combination with standard therapeutic agents cetuximab and chemotherapy on colon tumor cells.Study Design: Descriptive studyPlace and Duration of Study: This study was conducted at the College of Medicine, University of Babylon, Iraq from 1st December 2024 to 30th May 2025.Methods: Cells were exposed to various doses of attenuated MV, cetuximab, 5-fluorouracil, and cisplatin. Viability, apoptosis (caspase-3 levels), and immune markers (IFN-γ, TGF-β, IL-10, TNF-α) were assessed using biochemical assays to identify optimal therapeutic ratios.Results: Cetuximab alone increased caspase-3 levels, while combination therapies induced greater cell death through alternative mechanisms. MV markedly elevated IFN-γ (55.50±12.10 vs. 24.15±3.73, P < 0.001). Combination treatments suppressed immunosuppressive cytokines; TGF-β was significantly reduced in the measles virus cisplatin group (0.161±0.001 vs. 0.182±0.002, P = 0.005), and IL-10 and TNF-α levels were lowered dose-dependently, with triple combinations achieving near-complete suppression (5.00±0.80 vs. 203.63±22.19, P <0.001). Conclusion: Measles virus based combination therapy produces potent immunomodulatory effects, enhancing anti- tumor action beyond apoptosis by reducing immunosuppressive cytokines and controlling inflammation. Optimizing dose ratios and ensuring clinical safety remain crucial for future applications.

Oral triple combination lipid-lowering therapy and LDL cholesterol goal attainment: A simulation using the SANTORINI study cohort.

Relative particle size and distribution of inhaled triple therapies.

Increased resistance to β-lactams/β-lactamase inhibitors by mutations in β-lactamase genes, porins, and efflux pumps complicates the management of carbapenem-resistant Klebsiella pneumoniae (CRKP). Polymyxin B (PMB)-based combination therapy is the best alternative treatment for middle and low-income countries that cannot access the latest medicines. It is crucial to know both phenotypic and genotypic characteristics of a pathogen to understand the killing effect of each drug and its combinations. Hence, our objective was to incorporate mechanistic insights gained from resistance mechanisms of each isolate to develop a mechanism-based pharmacokinetic/pharmacodynamic model. Six clinical CRKP isolates with diverse genotypic resistance expressing blaKPC, blaNDM, porin, and mgrB mutations were used for static concentration time kill (SCTK) assays to evaluate the rate and extent of killing by monotherapy, double and triple combinations using PMB (0.5-64 mg/L), meropenem (10-120 mg/L), and fosfomycin (75-500 mg/L). Isolate BRKP28 expressed non-functional MgrB (a regulatory protein) and high-level phenotypic resistance (PMB MIC: >128 mg/L). In line with the observed resistance, the model estimated that BRKP28 had a reduced maximum killing rate constant for PMB (3.61 h⁻¹) relative to other isolates. The mechanistic synergy of PMB, due to outer membrane disruption, was incorporated into three isolates with porin mutations. PMB demonstrated 83%-88% mechanistic synergy with meropenem and 81%-98% with fosfomycin. The model further estimated that a very low concentration of PMB (0.49-0.64 mg/L) was sufficient to achieve 50% of the maximum synergy. Simulations using population pharmacokinetic models showed that combination therapy of PMB (1 mg/kg q12h) and fosfomycin (8 g q8h) achieved >73% reduction in area under the bacterial load-versus-time curve across four isolates. The triple combination therapy achieved a 67.7% reduction in non-carbapenamase producing isolate. These findings demonstrates that a low PMB dosing regimen (1 mg/kg q12h) can produce synergistic effects in combination therapy and may be effective in managing infections caused by CRKP, including PMB resistant isolates.

Cystic fibrosis (CF) is a genetic disorder caused by mutations in the CFTR gene, leading to multi-system impairment. Sleep respiratory disorders (SRDs) are frequent in individuals with CF—even in those with normal or mildly impaired lung function—and may adversely affect overall health. The triple combination of elexacaftor, tezacaftor, and ivacaftor (ETI) has markedly improved clinical outcomes in CF; however, its long-term impact on SRDs remains unclear. This study aimed to assess the effects of ETI on nocturnal cardiorespiratory parameters in individuals with CF over a two-year period. Thirty-five clinically stable patients aged ≥13 years, eligible for ETI therapy, were enrolled. Nocturnal cardiorespiratory polygraphy and spirometry were performed at baseline (T0), one year (T1), and two years (T2) after ETI initiation. After one year, significant improvements were observed in mean oxygen saturation (mSpO2), time with SpO2 ≤ 90% (t ≤ 90%), and respiratory rate. Spirometric indices (FEV1, FVC, FEF) also significantly increased (p < 0.05). Correlation analysis revealed positive associations between mSpO2 and FEV1 (ρ = 0.515, p = 0.002) and between FEV1 and FVC (ρ = 0.894, p < 0.001), while t ≤ 90% negatively correlated with FEV1 (ρ = −0.404, p = 0.016). No additional significant changes were found at T2. ETI therapy resulted in sustained improvements in nocturnal oxygenation and lung function, supporting the importance of nocturnal respiratory monitoring during follow-up.

INTRODUCTION. Valsartan+sacubitril (a combination of neprilysin inhibitor and angiotensin II receptor blocker) effectively reduces blood pressure (BP) and has the potential to improve metabolic parameters. However, despite this class of drugs being included in clinical guidelines, the specific indications in patients with arterial hypertension are not clearly defined, thus requiring a more detailed study. AIM. This study aimed to assess valsartan+sacubitril combination used for treatment of arterial hypertension in adults in outpatient settings, specifically regarding its efficacy, safety, and impact on overall clinical outcomes and quality of life. MATERIALS AND METHODS. The study is an open prospective longitudinal observation with active control. The study was conducted at State Autonomous Healthcare Institution “City Polyclinic No. 12” (city of Tyumen, Tyumen region). Patients were recruited from 01.10.2022 till 31.03.2025. For each patient, the observation period was 3 months for stage 1 ( n =550) and 1 year for stage 2 ( n =160). BP was controlled at the inclusion, at the end of stage 1, and after 3, 6, and 12 months of treatment. At stage 1, patients were divided into 4 groups: angiotensin-converting-enzyme inhibitor (ACE) + diuretic ( n =189), ACE inhibitor + calcium channel blocker (CCB) ( n =121), angiotensin II receptor blocker (ARB) + diuretic ( n =119), ARB + CCB ( n =121). At stage 2, patients not achieving target BP ≤140/90 mmHg ( n =160) were randomised into 2 groups: study group ( n =80), patients receiving valsartan+sacubitril + diuretic/CCB; and control group ( n =80), receiving a triple combination of ARB + diuretic + CCB or ACE inhibitor + diuretic + CCB. RESULTS. At stage 2, the rate of patients achieving target BP was 93% in the study group vs. 83% in the control group after 3 months; 94% vs. 88% after 6 months; and 99% vs. 98% after 12 months, respectively. Average daily systolic blood pressure and diastolic blood pressure after 3 months of treatment had a statistically significant difference in favour of the study group ( p &lt;0.05). Noteworthy is the positive effect on the reduction of peak average daily systolic, diastolic, as well as pulse BP, and blood pressure load ( p &lt;0.001). After 6 months, the difference between the groups remained the same for all the decreasing parameters (according to 24-h blood pressure monitoring). Only after 12 months did patients in the control group receive a comparable reduction in the parameters; no statistically significant differences were revealed ( p &gt;0.05). EQ-5D showed higher quality of life in the study group after 12 months, the average score being 0.82±0.08 vs. 0.69±0.10 in the control group (change +0.17 vs. +0.05; p &lt;0.05). All adverse reactions for valsartan+sacubitril were predictable; the differences in the frequency of treatment discontinuation between the groups were not statistically significant. CONCLUSIONS. Valsartan+sacubitril has demonstrated efficacy and safety in hypertension in adults. This combination can be recommended as a second-line treatment in case of ineffective two-component regimens of the first-line antihypertensive therapy.

Combined CDK4/6 inhibitor (CDK4/6i) and endocrine therapy (ET) improves outcomes in advanced estrogen receptor-positive (ER+) breast cancer, but emergence of resistance to this combination underscores the pressing need for alternative therapeutic strategies. A promising approach involves adding an inhibitor of the PI3K/AKT/mTOR pathway to the standard combined CDK4/6i and ET, but selecting the most effective inhibitors and their optimal combinations has proven to be challenging. Here, we compared the efficacy of various triple combinations using single- or dual-point PI3K/AKT/mTOR pathway inhibitors in breast cancer cell lines, cell line xenografts, patient-derived xenografts, and organoids resistant to CDK4/6i and ET and exhibiting PIK3CA, PTEN, or AKT1 mutations. PIK3CA-mutant, PTEN-wild type, CDK4/6i-resistant, and ET-resistant models required the addition of the dual PI3K/mTOR inhibitor gedatolisib to effectively impede tumor growth by blocking the HIF-1α pathway through both mTORC1 inhibition and PI3K/AKT-mediated modulation of GSK3α/β activity. Conversely, PIK3CA-wild type, PTEN-null cells benefited from triple combinations incorporating either the AKT inhibitor capivasertib or the dual mTORC1/2 inhibitor sapanisertib to block tumor growth. In addition, gedatolisib reduced viability of PIK3CA- or AKT1-mutant and PTEN-wild type CDK4/6i-resistant patient-derived organoids compared with the α-specific PI3K inhibitor alpelisib. Our data support the higher efficacy of gedatolisib over alpelisib in ER+ breast tumors harboring alterations of the PI3K/AKT/mTOR pathway including PIK3CA or AKT1 mutations.

FDA-approved oncolytic herpes simplex virus-1 (oHSV) therapy has emerged as an effective viro-immunotherapy for solid tumors. However, tumor- and tumor microenvironment (TME)-associated adaptations following viral treatment, such as feedback immune suppression, neoangiogenesis, and enhanced tumor aggressiveness, often hinder complete tumor eradication. Gaining a deeper understanding of the molecular mechanisms that limit the therapeutic efficacy of oHSV will be crucial to enhancing its clinical impact. We recently discovered that oHSV induces Insulin-like growth factor 2 (IGF2) secretion, shaping an immunosuppressive TME. Similarly, radiotherapy (RTx) activates the IGF1/IGF1R and YAP1 signaling pathways, further promoting therapeutic resistance. In this study, we investigated how oHSV-induced IGF1R/YAP1 signaling influences feedback pro-survival and proliferative pathways in tumor cells and evaluated the therapeutic potential of combining IGF1R blockade with oHSV and RTx.We first demonstrated that oHSV activates IGF1R signaling in vitro and in vivo, promoting tumor proliferation. While IGF1R-targeted monotherapies showed limited cytotoxic effects, combining IGF1R inhibitors with oHSV led to a significant, albeit modest, increase in cytotoxicity across tested in vitro breast cancer (BC) and primary glioblastoma (GBM) cells and in vivo xenograft models. Furthermore, we observed that co-treatment with oHSV and RTx robustly activated both IGF1R and YAP1 in resistant cells, revealing the IGF1R/YAP1 axis as a key mediator of resistance to dual oHSV and RTx therapy. Notably, the triple combination of oHSV, RTx, and IGF1R blockade yielded synergistic anti-tumor effects, abolished YAP1 expression, and significantly enhanced survival in orthotopic BC and GBM models. Collectively, these findings provide a strong rationale for the clinical evaluation of triple-combination therapy as a synergistic strategy to enhance the anti-tumor efficacy of oHSV and overcome RTx resistance in patients with BC and GBM.

Background: Chronic obstructive pulmonary disease (COPD) is a progressive respiratory condition with significant economic burden, morbidity, and mortality rates worldwide. In the Kingdom of Saudi Arabia (KSA), 4.2% of adults 40 years and older have COPD, with a higher prevalence in men and older populations. Key risk factors include smoking, air pollution, occupational exposures, and genetics. COPD coexists with cardiovascular disease (CVD) often, making diagnosis and management more difficult. This study proposes two referral algorithms to optimize care for COPD patients with coexisting CVD in the KSA. Methods: A nine-member cardiopulmonary task force reviewed pertinent literature, guidelines, and held virtual meetings from April to August 2025. Every algorithmic component was iteratively refined; consensus was reached when at least 80% of participants agreed, and items not reaching this threshold were revised until full agreement was reached. Results: According to the cardiology-to-pulmonology algorithm, patients who have unidentified respiratory symptoms or COPD risk factors undergo spirometry assessment and, if confirmed, are referred to pulmonology for diagnostic confirmation, phenotyping, and treatment, including triple fixed-dose combination therapy (TFDC) when necessary. On the other hand, the pulmonology-to-cardiology algorithm directs the evaluation of CVD risk factors and comorbidities using clinical evaluation, electrocardiogram, echocardiography, and biomarker testing, for cardiology referral. Conclusions: By establishing bidirectional referral pathways, morbidity and healthcare burden can be decreased, early detection can be improved, and multidisciplinary management can be strengthened. Future research should assess the feasibility, cost-effectiveness, and real-world impact within KSA’s healthcare system.

Objective: This study aimed to investigate the antimicrobial, anti-inflammatory, antioxidant, and anti-apoptotic effects of Graviola (Annona muricata), Moringa oleifera, and Lactobacillus gasseri, alone and in combination, against Pseudomonas aeruginosa in vitro wound infection model. Methods: Antibacterial activity tests against Pseudomonas aeruginosa was determined using the Kirby-Bauer disk diffusion method, MIC/MBC, and FIC methods. Biofilm inhibition was measured by crystal violet staining. A scratch wound model using fibroblast cell line was infected with Pseudomonas aeruginosa. Following treatment with the extracts, cell viability, oxidative stress, cytokine levels (IL-1beta, IL-10 via ELISA), and apoptotic gene expression (BAX, BCL-2 via qPCR) were evaluated. Results: The triple combination (Graviola + Moringa + Lactobacillus gasseri) showed the strongest antibacterial activity (23 mm zone; FIC = 0.25) and notable antibiofilm effects. In infected fibroblasts, cell viability increased to with combination treatment, approaching control levels. TOS levels decreased significantly while TAC increased, indicating reduced oxidative stress. IL-1beta levels were significantly lowered, and IL-10 levels were restored. Additionally, BAX gene expression decreased by 47%, and BCL-2 increased by 50% in the triple treatment group, suggesting protection against apoptosis. Conclusion: The combined application of Graviola, Moringa oleifera, and Lactobacillus gasseri exerts synergistic antimicrobial, anti-inflammatory, antioxidant, and anti-apoptotic effects against Pseudomonas aeruginosa induced wound infection. These results will shed light on the search for alternative natural therapeutic strategies, particularly in the treatment of chronic wounds associated with antibiotic-resistant pathogens.