Epilepsy is one of the most prevalent and disabling neurological disorders, affecting >50 million people worldwide. Beyond recurrent seizures, it is strongly associated with cognitive impairment, psychiatric comorbidities, reduced social participation, and a markedly increased risk of premature death. Although considerable advances in neuroimaging, pharmacology, and surgical techniques have expanded therapeutic possibilities, nearly one-third of patients remain refractory to current treatments, a challenge that highlights the pressing need for deeper mechanistic insights and innovative therapeutic strategies. This review provides an integrated overview of recent progress in epilepsy research and treatment. At the molecular level, we examine how ion channel dysfunction, receptor abnormalities, and disrupted signaling pathways drive hyperexcitability. We highlight insights from genetics and acquired etiologies that illuminate disease heterogeneity. We address prevailing hypotheses of drug resistance and potential biomarkers. We also emphasize the growing recognition of epilepsy’s close association with diverse comorbidities, where shared molecular pathways not only deepen our understanding of disease mechanisms but also highlight new therapeutic targets. Finally, we evaluate emerging therapeutic directions, including precision pharmacology, neuromodulation, gene and cell therapies, and metabolic approaches such as the ketogenic diet. By bridging epidemiological perspectives with mechanistic discoveries and innovative therapies, this review underscores how advances in epilepsy research are reshaping the path toward precision medicine and improved patient outcomes.
Oculo-Cerebro-Renal-Lowe syndrome, caused by loss of the PI(4,5)P₂ 5-phosphatase OCRL, is a rare and severe disorder that lacks curative therapy. By integrating deep cell-biological insight into endosomal trafficking and proximal tubule protein reabsorption with high-content screening across engineered cell lines, patient-derived proximal tubule cells, human kidney organoids, and a humanized mouse model, we identify IB-MECA, an oral adenosine A3 receptor agonist, as a targeted therapy poised for clinical evaluation. IB-MECA normalizes endosomal PI(4,5)P₂ homeostasis, restores receptor trafficking, and rescues protein reabsorption in all systems, demonstrating the translational power of a mechanism-anchored, cross-species screening pipeline that couples cellular correction to organ-level benefit and supports rapid progression toward phase II testing pending regulatory approval. Mechanistic dissection revealed that IB-MECA acts through A3AR-dependent activation of PLC, revealing a previously unrecognized axis whereby receptor-driven hydrolysis of plasma-membrane PI(4,5)P₂ corrects pathological endosomal PI(4,5)P₂ accumulation. This receptor-mediated rewiring of phosphoinositide homeostasis contrasts with earlier strategies based on broad kinase inhibition and establishes plasma-membrane GPCR–PLC signaling as a precise, druggable entry point to correct endolysosomal lipid imbalance. Together with the favorable clinical safety record of IB-MECA, these findings provide a compelling rationale for an imminent clinical trial (NCT07410455) in Lowe syndrome and outline a generalizable, cell biology–guided framework for developing therapies for inherited disorders of phosphoinositide metabolism.
Gemcitabine resistance remains a major therapeutic barrier in pancreatic ductal adenocarcinoma (PDAC), for which median survival in advanced disease has remained near one year despite extensive clinical investigation. Using artificial intelligence (AI)-guided structure-based drug repurposing, we identified sitagliptin, a DPP-4 inhibitor for diabetes, as a candidate ribonucleotide reductase (RRM1/2) inhibitor that sensitizes PDAC to gemcitabine. Molecular dynamics simulations suggested that sitagliptin disrupts gemcitabine-RRM1/2 interactions, downregulating RRM1/2 expression and restoring chemosensitivity across PDAC cell lines, patient-derived organoids, and mouse models. Sitagliptin enhanced the anti-tumor efficacy of both gemcitabine-nab-paclitaxel (GnP) and FOLFIRINOX regimens in preclinical studies. We conducted SITGEM-CARE, a single-center phase 2 trial in 22 patients with locally advanced or metastatic PDAC (median age 65.0 years; ECOG performance status 1, 86.4%; Stage IV, 68.2%; liver metastases, 54.5%). Patients received sitagliptin 100 mg orally once daily continuously, plus gemcitabine 1000 mg/m² and nab-paclitaxel 125 mg/m² on days 1 and 8 of 21-day cycles. Among 22 evaluable patients, eight achieved a partial response, and 11 had stable disease, yielding an objective response rate of 36.4% (95% CI: 17.2–59.3%) and a disease control rate of 86.4% (95% CI: 65.1–97.1%), with tumor shrinkage in 86.4% of patients. At a median follow-up of 9.9 months, the median progression-free survival was 6.6 months (95% CI: 4.8–12.4) with 6-month and 9-month PFS rates of 63.6% and 43.5%, respectively. Median overall survival was 12.5 months (95% CI: 7.8-not reached), with 62.9% of patients alive at 12 months. Furthermore, treatment was well tolerated, with no Grade 4/5 treatment-related adverse events. These findings are hypothesis-generating and warrant confirmation in adequately powered, randomized trials. ClinicalTrials.gov: NCT05947825.
Dear Editor , In this study, we aimed to characterize IgG, IgM and complement fractions deposition in the BM of low-risk myelodysplastic syndrome (LR-MDS) 1 patients by immunohistochemistry and fl ow cytometry to assess the role of complement and humoral immunity on ineffective erythropoiesis and its clinical implications. Furthermore, we investigated the expression of complement related genes in MDS versus healthy donors by single-cell RNA sequencing, with the goal of de fi ning whether complement activation represents a recurrent and targetable feature of LR-MDS. The study was approved by the Ethics Committees of Human Experimentation, and patients gave informed consent in accordance with the Declaration of Helsinki. We included 44 patients (73% male) with a median age at diagnosis of 76 years (interquartile range [IQR], 68 – 82 years). Risk
