Although pesticide exposure has been linked to worse motor symptoms in Parkinson's disease (PD), its associations with non-motor burden and with post-diagnostic progression rate remain unclear. We analyzed two large longitudinal cohorts, PPMI Online (n = 7190) and Fox Insight (n = 2298), using linear mixed-effects models and Cox regression, with supportive triangulation in an EHR cohort. In PPMI Online, pesticide exposure was associated with higher MDS-UPDRS Part II scores (β = 1.97, 95% CI 1.34-2.60), lower PDAQ-15 scores (β = -2.40, 95% CI -3.23 to -1.57), and greater anxiety, daytime sleepiness, and sleep disturbance. Motor and cognition-related estimates were directionally similar in Fox Insight. Time interaction estimates showed no consistent exposure-related differences. Primary Cox models indicated earlier motor milestones in both cohorts and earlier sleepiness and anxiety milestones in the PPMI Online cohort. Co-exposure to more pesticide classes was associated with worse motor function in both cohorts. TriNetX also showed elevated risks across five ICD-coded symptom domains (RRs 1.44-1.87), although these findings should be interpreted cautiously because the outcomes were defined differently. Further longitudinal studies using harmonised exposure assessments and repeated multidomain measures are needed to clarify the relationship between pesticide exposure and symptom trajectories after PD diagnosis.

Drug safety remains a central challenge in drug development and post-marketing surveillance, as the limited size and duration of pre-approval trials constrain detection of rare or delayed adverse effects, leaving patients exposed to residual risk after launch. Using ProTox 3.0 in silico toxicity predictions and statistical modeling, we analyzed an observational cohort of nearly 2,000 historically marketed small-molecule drugs and identified hepatotoxicity as a robust and consistent determinant of pharmaceutical post-marketing withdrawal probability after adjustment for therapeutic context. Other organ toxicities and structural descriptors of the drug molecules exhibited additional, indication-specific associations with withdrawal status, indicating that ex-ante toxicity liability is heterogeneous across therapeutic areas. While our analysis does not establish causality, the stable correlations observed across toxicity profiles, structural characteristics, and clinical indications suggest that a substantial fraction of withdrawal risk is statistically predictable. Embedding these quantitative risk signals into early-stage decisions and targeted safety evaluation strategies offers a data-driven approach to reduce late-stage attrition and post-marketing withdrawals, thereby contributing to safer and more efficient drug development.

e17019 Background: Androgen Receptor Pathway Inhibitors (ARPIs) are commonly used in metastatic prostate cancer (mPC). Given the advanced age and comorbidity burden typical of this population, polypharmacy is frequent in mPC patients, increasing the risk of clinically relevant drug–drug interactions (DDIs), which are rarely assessed in routine practice. The Drug-PIN software, an intelligent system analyzing phenotypic data and DDIs, has been shown to identify patients at risk of severe toxicity or reduced survival. The DDI-AID study investigates the association of DDIs with survival in patients with mPC treated with ARPI in a real-world setting. Methods: DDI-AID is an Italian, multicenter, retro-prospective observational study. The study included 245 consecutive patients with mHSPC or mCRPC treated with ARPI, and receiving at least one concomitant medication. Clinically relevant DDIs were assessed at ARPI initiation and patients were classified into no / low- or high-risk-DDIs groups. Progression-free Survival (PFS) was defined as time from ARPI start to disease progression or death. Survival analyses were performed using Kaplan-Meier and Cox proportional hazards models were adjusted for relevant clinical covariates. The study was approved by Ethical Committee Lazio Area 1 (Ref. n. 7364, 2023/11/08). Results: At the data cut-off (15 January 2026), a total of 245 patients were included. The median age was 74 years (range 52–94), and the median Charlson Comorbidity Index (CCI) was 3 (range 1-8). Polypharmacy was observed in 116 patients (47%), and high-risk DDIs were identified in 80 patients (33%). Regarding treatments, 68 (28%) patients received Abiraterone, 97 (39%) Enzalutamide, 71 (29%) Apalutamide and 9 (4%) Darolutamide with Docetaxel. A total of 138 (56%) patients received ARPI in the mHSPC setting and no significant differences were observed in the ADT received (p = 0,093). The median PFS was 35.9 months (95% CI 27.8-NR) in the low-risk-DDI group compared to 19.8 months (95% CI 15.1-NR) in the high-risk DDI group. In the multivariable analysis, adjusted for age (≤74 vs ≥75 years), performance status (0 vs 1–3), Charlson Comorbidity Index (0–1 vs ≥2), and presence of visceral metastases, the presence of low-risk DDIs remained significantly associated with longer PFS (HR 0.59, 95% CI 0.38–0.90, p = 0.016). Moreover, treatment with ARPIs in the mHSPC setting (HR 0.49, 95% CI 0.31–0.78, p = 0.003) and achieving a PSA nadir ≤2 ng/mL (HR 0.16, 95% CI 0.09–0.26, p < 0.001) were independently associated with longer PFS. Conclusions: In this real-world cohort, DDIs are common in patients treated with ARPIs and the presence of high-risk DDIs was associated with reduced PFS. These findings highlight the importance of medication review in routine clinical practice.

Bitter taste receptors (TAS2Rs) are increasingly recognised as extraoral chemosensors that modulate diverse biological processes, including cancer cell behaviour and drug responsiveness. Many TAS2R ligands correspond to therapeutic compounds; however, their contribution to the response of brain tumours to chemotherapy remains unexplored. Here, we investigated whether the bitter taste signalling pathway is modulated by temozolomide (TMZ), the standard chemotherapeutic agent for glioblastoma, with an impact on treatment efficacy in glioblastoma cells. We show that TMZ elicits intracellular Ca2+ responses compatible with activation of G-protein-coupled receptor signalling and induces anti-proliferative and pro-apoptotic effects in multiple human glioblastoma cell lines. Pharmacological inhibition of bitter taste receptors, as well as genetic silencing of the taste transduction G protein GNAT3, significantly attenuated TMZ-induced cytotoxicity, suggesting that bitter taste signalling is involved in this process. In silico ligand prediction combined with receptor expression profiling identified TAS2R43 as a candidate modulator of these effects, and TAS2R43 knockdown markedly reduced TMZ-induced loss of cell viability and apoptosis. Moreover, TMZ enhanced intracellular accumulation of the ABC transporter substrate doxorubicin, suggesting modulation of multidrug efflux mechanisms. Collectively, our findings identify TAS2R43 as a potential biomarker that warrants further validation to improve responses to TMZ and other ABC transporter-limited anticancer drugs.

Identifying allergenic proteins in raw materials can help reformulate products to make them safer for sensitive populations. Computational tools are powerful for identifying the allergenic potential of proteins and chemicals in food and personal care products. These tools can help minimize allergic risks and guide safer product development by leveraging sequence analysis, structural modelling, and epitope mapping. Food allergens can sometimes impact how a drug is processed or worsen allergic responses. These interactions can pose significant health risks and complicate treatment plans. In addition to this, certain foods can influence how drugs are absorbed, metabolized, or broken down in the body. While not all interactions trigger allergies, they may amplify reactions or side effects. Cross-reactivity occurs when proteins in foods share structural similarities with components in certain drugs, leading the immune system to react to both mistakenly. Here, we present AllergyPred, a web server that predicts both protein- and chemical-based allergens. Five different models take protein IDs, sequences, chemical IDs, and structures as inputs for predicting respective allergy endpoints. The AllergyPred web server is free and open to all users, and there is no login requirement. It can be accessed via https://allergypred.charite.de/AllergyPred/. The prediction results will be presented in the form of a table and can be downloaded in several file formats supporting users to report the results for the respective projects.

The unique pharmacokinetics of BRAF and MEK inhibitors make patients vulnerable to drug-drug interactions (DDIs), which may compromise treatment efficacy in metastatic melanoma. This study evaluates the impact of DDIs on clinical outcomes in patients with metastatic melanoma treated with BRAF/MEK inhibitors. This multicenter, observational, retrospective study assessed DDIs using the Drug-PIN software. Associations between the Drug-PIN continuous score, Drug-PIN light, and treatment outscomes were analyzed along with the specific drugs involved in the DDIs. A total of 177 patients with BRAF-mutant metastatic melanoma undergoing BRAF/MEK inhibitor therapy were included. Of these, 94 patients (55.9%) were exposed to complex drug regimens related to comorbidities, supportive care, and symptom management. A significant change in Drug-PIN scores was observed before and after therapy initiation. Patients with low-grade DDIs demonstrated significantly longer median overall survival (OS) and progression-free survival (PFS) compared to those with high-grade DDIs (log-rank p = 0.0045 and p = 0.012, respectively); this observation was further validated by multiple regression analysis. By combining clinical and DDI data, we identified four patient subgroups with distinct prognoses, showing statistically significant differences in OS and PFS (log-rank p < 0.0001). The subgroup with the highest clinical risk and high DDI had markedly poorer outcomes (HR 2.87, 95% CI [1.7-4.8], p < 0.001). The drugs involved in high-level pharmacological interactions were analyzed. DDIs significantly contribute to poorer OS and PFS outcomes, independent of other clinical risk factors. Optimizing pharmacological regimens to minimize DDIs should be prioritized to enhance treatment efficacy in oncology. Prospective clinical trials are warranted to further validate the advantages of individualized, preemptive therapy optimization.

Bitter taste receptors (TAS2Rs) have a widespread expression in various extraoral organs where they detect the chemical composition of body fluids and trigger biological responses accordingly. Among the chemicals recognised by TAS2Rs there are natural and synthetic compounds including therapeutic drugs. We have shown that TAS2Rs are expressed in the blood-cerebrospinal fluid barrier where they regulate efflux transporters, thereby controlling the transport of compounds into the cerebrospinal fluid. More recently, we assessed the expression of these receptors in human glioblastoma cells, where 20 out of the 26 human TAS2Rs were identified. In this study, we investigated if temozolomide, the standard chemotherapy for glioblastoma, activates the bitter signalling pathway with impact in its therapeutic efficacy. Notably, we found that blocking the bitter taste signalling pathway significantly reduced the anti-proliferative and pro-apoptotic effects of temozolomide, and identified TAS2R43 as the receptor mediating these effects. We propose that upon ligand binding, TAS2R43 modulates multidrug resistance proteins (MDRs) activity, facilitating temozolomide entrance into glioblastoma cells. These findings underscore the importance of the taste transduction pathway in evaluating the chemical composition of the glioblastoma microenvironment. Furthermore, our data suggest that TAS2R43 could serve as a biomarker for the efficacy of temozolomide and other drugs that are substrates of MDRs. ### Competing Interest Statement The authors have declared no competing interest. Fundação para a Ciência e Tecnologia, PTDC/BIM-ONC/7121/2014, UID/Multi/00709/2013, UID/Multi/00709/2019, UI/BD/151025/2021 CENTRO 2020 and Lisboa 2020, POCI-01-0145-FEDER-016822 FEDER and COMPETE 2020, POCI-01-0145-FEDER-007491 CENTRO 2020, CENTRO-01-0145-FEDER-000013 Portuguese Platform of BioImaging, https://ror.org/0479zfq62, PPBI-POCI-01-0145-FEDER-022122

Treatment-resistant depression (TRD) remains a critical challenge in psychiatry, with limited effective options. Esketamine, a rapid-acting antidepressant, is usually combined with a selective serotonin reuptake inhibitor (SSRI) or a serotonin-norepinephrine reuptake inhibitor (SNRI), but comparative evidence of these combinations' effectiveness in real-world settings is sparse. To determine whether the combination of esketamine + SNRI shows differences in clinical outcomes compared to esketamine + SSRI in patients with TRD. This retrospective cohort study was conducted in September 2024 using data from the TriNetX global health research network, with a 5-year time window from the first esketamine trial. TriNetX data are drawn from real-world clinical settings and use electronic medical records from more than 90 health care centers across 20 countries. Adults with TRD who were treated with esketamine combined with either an SSRI or an SNRI were eligible for inclusion. Treatment with esketamine combined with an SSRI (citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, or vilazodone) or an SNRI (desvenlafaxine, duloxetine, levomilnacipran, milnacipran, or venlafaxine). The primary outcomes were all-cause mortality, hospitalization, depression relapse, and suicide attempts. Kaplan-Meier survival analysis was used to estimate survival probabilities, while risk ratios and odds ratios were calculated for all outcomes. In a population-based sample of 61 882 adult participants with TRD who were treated with esketamine combined with either an SSRI or an SNRI, 55 480 participants were selected after applying propensity score matching for age and sex. These patients were divided into 2 matched cohorts: 27 740 patients treated with esketamine + SSRI (16 007 female participants [57.7%]; mean [SD] age, 46.0 [21.3] years) and 27 740 treated with esketamine + SNRI (16 242 female participants [58.6%]; mean [SD] age, 45.9 [21.9] years). In the entire study population, the incidence of mortality, hospitalizations, depressive relapses, and suicide attempts was low throughout the study period. Patients in the esketamine + SNRI group had significantly lower all-cause mortality (5.3% vs 9.1%; P < .001), hospitalization rates (0.1% vs 0.2%; P < .001), and depression relapses (14.8% vs 21.2%; P < .001) compared to the esketamine + SSRI group, which instead showed a lower incidence of suicidal attempts (0.3% vs 0.5%; P = .04). In this retrospective comparative effectiveness study, among the study sample, incidence of mortality, hospitalizations, depressive relapses, and suicide attempts was low. The esketamine + SNRI group showed lower incidence of mortality, hospitalizations, and depressive relapses, while the esketamine + SSRI group showed a slightly lower incidence of suicidal attempts.

Oral lichen planus (OLP) and oral lichenoid lesions (OLL) are immune-mediated conditions that may occur in response to medications or vaccines. Although hepatitis B vaccination is widely considered safe, isolated case reports have suggested a possible link to OLP/OLL. However, large-scale epidemiologic data are lacking. A matched-cohort study was conducted using real-world data from the TriNetX database. The initial dataset included 112,444 patients who received hepatitis B vaccination and 7,002,541 unvaccinated individuals. After one-to-one propensity score matching, each cohort comprised 112,444 subjects. The primary outcome was the onset of OLP/OLL within 30 days post-index, identified via ICD-10 codes and confirmed histologically. OLP/OLL occurred in 423 vaccinated patients (0.736

OBJECTIVES:Databases specifying the nutrients and allergens present in multi-ingredient foods are required to explore the effect of food consumption on health outcomes accurately. The phytochemicals found in tree nuts have been associated with antioxidant, anti-inflammatory, antiproliferative, antiviral, chemo preventive and hypercholesterolaemic actions, all of which are known to affect the initiation and progression of several pathogenic processes. We have developed KNUTS-DB - a data-driven knowledge database for nuts - containing information on the chemical nutrients, molecular targets, pathways, disease associations, and clinically defined food allergen properties of peanuts and tree nuts. METHODS:The database includes data sets associated with extremely rich and diverse metadata on almonds, cashew, pecan, walnut, pistachio, peanut and walnut. Additionally, the database allows users to perform pathway and GO-Term enrichment analysis for user-defined chemical nutrients. The results of the analysis are presented using heatmaps and network plots. RESULTS:The database can be searched using options such as similarity search, interaction values, type of allergens, and specific nut types. KNUTS-DB offers researchers a unique platform to explore nuts' chemical composition and to investigate associations between nut composition and health outcomes - providing deeper insights into the molecular mechanisms. CONCLUSIONS:KNUTS-DB, the first of its kind, is freely available to all users via https://allergypred.charite.de/KNutsDB/ without any login or registration.

BACKGROUND:Platelet-activating factor (PAF)-induced pulmonary endothelial barrier failure is mediated by acid sphingomyelinase (ASM) translocation to caveolae. ASM, however, lacks a transmembrane domain for anchoring inside caveolae. We hypothesised that ASM anchors to cation-independent mannose-6-phosphate (M6P) receptor (CI-M6PR) in caveolae, from where it can be competitively released by M6P. METHODS:We explored ASM-CI-M6PR interactions using co-immunoprecipitation and proximity ligation assay in isolated lungs and human pulmonary microvascular endothelial cells. ASM release by M6P was determined in human pulmonary microvascular endothelial cells, isolated lungs and in vivo. The effects of M6P on 1) PAF-induced lung oedema formation and endothelial Ca2+ concentration and 2) lung injury in acid instilled, overventilated mouse lungs were examined. ASM levels were measured in serum and bronchoalveolar lavage fluid of patients with acute respiratory distress syndrome. The TriNetX database was probed for associations of ASM-inhibiting tricyclic antidepressants with outcomes. RESULTS:Co-immunoprecipitation and proximity ligation assay revealed an ASM interaction with CI-M6PR in endothelial caveolae, which was further increased by PAF. M6P, but not glucose-6-phosphate, caused ASM release, thereby decreasing ASM content and activity in caveolae in vitro, in situ and in vivo. Analogously, M6P, yet not glucose-6-phosphate, attenuated PAF-induced endothelial Ca2+ influx and lung oedema in situ, and acute lung injury in vivo. ASM levels were increased in serum but not bronchoalveolar lavage fluid in patients with acute respiratory distress syndrome. Use of tricyclic antidepressants was associated with better outcomes in patients with severe respiratory infections. CONCLUSIONS:CI-M6PR anchors ASM in caveolae. M6P may hence present a promising target in ASM-related lung injury and oedema.

Clostridioides difficile is a leading cause of healthcare-associated infection, and an unacceptably high proportion of patients with C. difficile infection die despite conventional antibiotic treatment. Host-directed immunotherapy has been proposed as an ideal treatment modality for C. difficile infection to mitigate the underlying toxin-mediated pathogenic immune response while sparing protective gut microbes. Interleukin-23 monoclonal antibody inhibitors are used extensively to control pro-inflammatory Th17 immune pathways in psoriasis and inflammatory bowel disease that are similarly important during C. difficile infection. We used a large retrospective electronic health record database to test the hypothesis that hospitalized patients with C. difficile infection who are on anti-IL-23 treatment will have improved survival compared to patients without anti-IL-23. A total of 9,301 anti-IL-23 patients had significantly lower probability of all-cause death within 30 d (0.54%) compared with 1:1 propensity-matched control patients (3.1%). IL-23 inhibition is a promising adjunct to C. difficile treatment, and further clinical trials repositioning anti-IL-23 monoclonal antibodies from psoriasis and inflammatory bowel disease to C. difficile infection are warranted.

This study investigates treatment-resistant schizophrenia (TRS) by analysing genetic markers in dopamine and serotonin receptors. Conducted on a cohort of 221 patients with treatment-resistant mental disorders, the research focused on DRD2 and HTR2A gene variants-specifically, rs1801028, rs6314, rs7997012, and rs6311. The findings suggest specific associations between certain genetic variants and TRS. Notably, the HTR2A rs6314 A|G genotype and rs7997012 G|G genotype were significantly more prevalent in TRS patients compared to healthy controls (HCs). Haplotype analyses revealed associations between specific haplotypes-such as A|G (rs6314-rs7997012)-and TRS, indicating their potential predictive value for TRS versus HCs. The study underscores the involvement of the serotonergic system in TRS. These findings offer valuable insights into the genetic factors contributing to TRS, paving the way for future research and the development of personalised prevention and treatment strategies in psychiatry.

BackgroundThe aim of the present matched cohort study was to assess if patients using sodium-glucose cotransporter 2 inhibitors (SGLT2i) show an augmented risk of Fournier’s gangrene (FG) compared to subjects not using SGLT2i.MethodsRetrospective data were retrieved from the TriNetX database, whereby patients using SGLT2i and individuals not using SGLT2i were assigned to cohorts I and II, respectively. After matching for age, gender distribution, and prevalence of diabetes mellitus, human immunodeficiency virus infection, alcohol abuse, liver diseases, and use of immune suppressant, a risk analysis was carried out, and risk ratio (RR) and odds ratio (OR) were determined. The outcome was defined as diagnosis of FG.ResultsBefore matching, cohorts I and II accounted for 192,245 and 7,810,583 subjects. After matching, 192,245 patients (40.5% females and 59.5% males; mean age 67.5 ± 12.7 years) remained per cohort. Among the cohorts I and II, 186 and 312 individuals were diagnosed with FG. The according risks of 0.1% and 0.2% were significantly different (p > 0.001; Log-Rank test). RR and OR were 0.539 (95% CI 0.447-0.650) and 0.539 (95% CI 0.446-0.650).ConclusionThe present study found a significantly lower risk of FG in patients using SGLT2i in comparison with subjects not using SGLT2i. Due to specific limitations that come alongside with the applied study design, this result needs to be interpreted most cautiously. As the cohorts were matched for the frequency of diabetes mellitus (68.9% of the cohorts I and II) this risk factor for FG might have been mitigated among the individuals in cohort I due to the use of SGLT2i, which may in turn explain the abovementioned finding.

This study investigates the role of genetic variations in the 5-Hydroxytryptamine Receptor 2A (HTR2A) gene in subjects with treatment-resistant obsessive–compulsive disorder (TR-OCD), compared to individuals with other treatment-resistant mental disorders (TRMDs). The goal is to explore whether specific HTR2A polymorphisms contribute to distinguishing TR-OCD from other TRMDs, thereby advancing our understanding of the underlying pathophysiological mechanisms. A retrospective observational study was conducted with 210 individuals affected by TRMDs (72 with major depressive disorder, 62 with bipolar disorder, 37 with schizophrenia, 30 with OCD, and 9 with other diagnoses). Genetic analyses focused on three HTR2A single nucleotide polymorphisms (SNPs) (rs6314, rs7997012, and rs6311), using next-generation sequencing from blood samples. Chi-square testing and single- and multiple-SNP analyses were employed to study the association between these SNPs and the TR-OCD diagnosis. The analysis revealed that the HTR2A rs7997012 A|A vs. G|G genotype was significantly associated with a higher likelihood of belonging to the TR-OCD group compared to other TRMDs, with an odds ratio of 6.85 (95

Background In the modern era, the growth of scientific literature presents a daunting challenge for researchers to keep informed of advancements across multiple disciplines. Objective We apply natural language processing (NLP) and embedding learning concepts to design PubDigest, a tool that combs PubMed literature, aiming to pinpoint potential drugs that could be repurposed. Methods Using NLP, especially term associations through word embeddings, we explored unrecognized relationships between drugs and diseases. To illustrate the utility of PubDigest, we focused on chronic thromboembolic pulmonary hypertension (CTEPH), a rare disease with an overall limited number of scientific publications. Results Our literature analysis identified key clinical features linked to CTEPH by applying term frequency-inverse document frequency (TF-IDF) scoring, a technique measuring a term’s significance in a text corpus. This allowed us to map related diseases. One standout was venous thrombosis (VT), which showed strong semantic links with CTEPH. Looking deeper, we discovered potential repurposing candidates for CTEPH through large-scale neural network-based contextualization of literature and predictive modeling on both the CTEPH and the VT literature corpora to find novel, yet unrecognized associations between the two diseases. Alongside the anti-thrombotic agent caplacizumab, benzofuran derivatives were an intriguing find. In particular, the benzofuran derivative amiodarone displayed potential anti-thrombotic properties in the literature. Our in vitro tests confirmed amiodarone’s ability to reduce platelet aggregation significantly by 68% (p = 0.02). However, real-world clinical data indicated that CTEPH patients receiving amiodarone treatment faced a significant 15.9% higher mortality risk (p<0.001). Conclusions While NLP offers an innovative approach to interpreting scientific literature, especially for drug repurposing, it is crucial to combine it with complementary methods like in vitro testing and real-world evidence. Our exploration with benzofuran derivatives and CTEPH underscores this point. Thus, blending NLP with hands-on experiments and real-world clinical data can pave the way for faster and safer drug repurposing approaches, especially for rare diseases like CTEPH.

Metabolomic microbiome research has become an important topic for understanding agricultural, ecological as well as health correlations. Only the determination of both the non-volatile and the volatile organic compound (mVOC) production by microorganisms allows a holistic view for understanding the complete potential of metabolomes and metabolic capabilities of bacteria. In the recent past, more and more bacterial headspaces and culture media were analyzed, leading to an accumulation of about 3500 mVOCs in the updated mVOC 4.0 database, including compounds synthesized by the newly discovered non-canonical terpene pathway. Approximately 10% of all mVOCs can be assigned with a biological function, some mVOCs have the potential to impact agriculture in the future (e.g. eco-friendly pesticides) or animal and human health care. mVOC 4.0 offers various options for exploring extensively annotated mVOC data from different perspectives, including improved mass spectrometry matching. The mVOC 4.0 database includes literature searches with additional relevant keywords, making it the most up-to-date and comprehensive publicly available mVOC platform at: http://bioinformatics.charite.de/mvoc.

Abemaciclib demonstrated clinical benefit in women affected by HR+/HER2− advanced breast cancer (aBC). Drug-drug interactions (DDIs) can lead to reduced treatment efficacy or increased toxicity. This retro-prospective study aimed to evaluate outcomes, DDIs’ impact, and toxicities of abemaciclib combined with endocrine therapy in a real-world setting. Patients from 12 referral Italian hospitals with HR+/HER2− aBC who received abemaciclib were included. Clinical data about comorbidities, concurrent medications, outcomes, and adverse events (AE) were collected. Drug-PIN® (Personalized Interactions Network) is a tool recognizing the role of multiple interactions between active and/or pro-drug forms combined with biochemical and demographic patient data. The software was used to define the Drug-PIN score and Drug-PIN tier (green, yellow, dark yellow, and red) for each patient. Univariate and multivariate analyses were performed to identify predictors of patients’ PFS or toxicity. One hundred seventy-three patients were included. 13% of patients had >75years. The overall response rate (ORR) was 63%. The general population’s median PFS (mPFS) was 22 months (mo), while mOS were not reached. Patients treated with abemaciclib in combination with AI and fulvestrant had a mPFS of 36 and 19 mo, respectively. The most common toxicities were diarrhea, asthenia, and neutropenia detected in 63%,49%, and 49% of patients. The number of concomitant medications and comorbidities were not associated with survival outcomes (22 vs 17 mo, p = 0.068, p = 0.99). Drug-PIN tier from dark yellow to red and Drug-PIN score >12 were associated with shorter PFS compared to no/low-risk DDIs and score <12 (15 vs 23, p = 0.005, p = 0.0017). Drug interaction was confirmed as an independent biomarker in a multivariate model (p = 0.02). No difference in any grade AE, severe toxicities, and diarrhea were detected among different age subgroups. No association was found between Drug-PIN score or Drug-PIN tier and overall toxicity (p = 0.44), severe AEs (p = 0.11), or drug reduction (p = 0.27). The efficacy and safety of abemaciclib plus ET were confirmed in a real-world setting, even in the elderly population and patients with comorbidities. Evaluation of DDIs with Drug-PIN appears to be an independent predictor of PFS.