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This special volume of Biochimica et Biophysica Acta - Molecular Basis of Disease showcases a transformative era in biomedical research, driven by the convergence of multi-omics technologies, artificial intelligence (AI), and systems biology. The volume is focused across eight thematic sections-spanning cancer, inflammatory and infectious diseases, neurodegeneration, cardiovascular health, autophagy, respiratory disease, and heme biology-this volume highlights how integrative methodologies are helping to simplify the complexity of disease mechanisms. These studies discuss not only biomarker discovery and disease mechanisms, but also how redox biology, lipidomics, machine learning, and proteogenomics are redefining pathophysiological frameworks. From spatial omics in colorectal cancer to ferroptosis in asthma and sepsis, these contributions demonstrate the translational power of different network analysis and validations. Key challenges-including standardization, ethical integration of AI, and global infrastructure gaps-are also addressed as future imperatives. Together, the articles in this volume serve not just as a repository of high-impact findings, but as an example of the roadmap toward precision medicine where diagnostics, therapies, and prognoses are tailored to the molecular individuality of each patient. This collection establishes BBA - Molecular Basis of Disease as a leading platform for next-generation disease biology and personalized healthcare innovation.

Activating PIK3CA mutations occur in approximately 40% of hormone receptor-positive (HR+)/HER2-negative breast cancers and represent a major driver of endocrine resistance. The PI3Kα-selective inhibitor alpelisib, in combination with fulvestrant, significantly improves progression-free survival in patients with PIK3CA-mutant disease, as demonstrated in the SOLAR-1 trial. However, this therapeutic strategy is frequently complicated by treatment-induced hyperglycemia, a metabolic disturbance that promotes oxidative stress, mitochondrial dysfunction, and inflammatory signaling, thereby increasing cardiovascular vulnerability. Sodium-glucose cotransporter-2 (SGLT2) inhibitors have emerged as cardiometabolic modulators with benefits extending beyond glucose lowering. In this study, we used a human cardiomyocyte in vitro model designed to recapitulate the hyperglycemic metabolic milieu observed in breast cancer patients receiving PI3Kα-targeted therapy, to investigate whether the SGLT2 inhibitor dapagliflozin directly protects cardiomyocytes from alpelisib- and fulvestrant-induced injury. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) were cultured under hyperglycemic conditions (25 mM glucose) to mimic the metabolic environment associated with PI3Kα inhibitor-induced dysglycemia. Cells were exposed to alpelisib (100 nM) and fulvestrant (100 nM), alone or in combination, in the absence or presence of dapagliflozin (1 μM). Cardiomyocyte viability was assessed using the MTS assay, mitochondrial function by TMRM-based mitochondrial membrane potential (ΔΨm) measurements, and apoptosis by caspase-3 quantification. Cardiomyocyte injury was evaluated by release of cardiac troponin I and heart-type fatty acid binding protein (H-FABP). Lipid peroxidation markers (MDA and 4-HNE) were measured to assess oxidative membrane damage. Intracellular inflammasome-related signaling (NLRP3 and MyD88) and secreted inflammatory mediators (IL-1β, IL-18, IL-6, TNF-α, and CCL2) were quantified by ELISA. Exposure to alpelisib, particularly in combination with fulvestrant, significantly reduced cardiomyocyte viability, induced mitochondrial depolarization, and increased caspase-3-mediated apoptotic signaling. These alterations were accompanied by elevated lipid peroxidation (MDA and 4-HNE) and increased release of cardiac injury biomarkers (troponin I and H-FABP). Alpelisib-based treatments also activated inflammasome-related signaling, as indicated by increased intracellular NLRP3 and MyD88 levels and enhanced secretion of pro-inflammatory mediators (IL-1β, IL-18, IL-6, TNF-α, and CCL2). Co-treatment with dapagliflozin significantly attenuated these alterations, preserving mitochondrial membrane potential, reducing apoptotic signaling, limiting oxidative membrane damage, and suppressing inflammatory cytokine release. This study provides evidence that alpelisib-based therapy under hyperglycemic conditions is associated with oxidative, mitochondrial, and inflammatory stress responses in human cardiomyocytes, recapitulating key features of cardiometabolic stress relevant to PI3Kα-targeted therapy. Importantly, dapagliflozin markedly attenuated these alterations, supporting a potential cardioprotective role that may extend beyond glycemic control. These findings provide a mechanistic rationale for further investigation of SGLT2 inhibition as a cardiometabolic protective strategy in patients receiving PI3Kα inhibitor-based cancer therapy.

Primary adrenal insufficiency (PAI) is a severe and potentially life-threatening condition characterised by the inability of the adrenal cortex to produce enough glucocorticoids and/or mineralocorticoids. The clinical signs of PAI are primarily due to deficient steroid hormone synthesis and include weight loss, orthostatic hypotension secondary to dehydration, hyponatremia, hyperkalaemia, and hypoglycaemia. In the paediatric population, PAI is most commonly associated with inherited monogenic disorders, particularly enzyme deficiencies. X-linked adrenal hypoplasia congenita (AHC) is a rare condition caused by deletions or single-nucleotide variants in the NR0B1 (DAX1) gene, which encodes the DAX1 protein expressed in the adrenal cortex, gonads, hypothalamus and pituitary gland. Although molecular genetics has significantly expanded our understanding of the aetiology of PAI, clinical diagnosis remains challenging when the initial hormonal findings are atypical, often delaying recognition and treatment. Pathogenic variants of DAX1 can lead to a spectrum of phenotypes, ranging from isolated adrenal insufficiency (AI) to complex syndromic presentations combining AI with hypogonadotropic hypogonadism and impaired spermatogenesis. Here, we report a case of a male patient with AI due to a de novo pathogenic variant in the NR0B1 gene. Furthermore, we provide a non-systematic review of the available literature on the diagnostic challenges facing and clinical variability in AHC, with a particular focus on the paediatric population. This case highlights the importance of a stepwise, comprehensive diagnostic approach to suspected PAI, particularly when initial biochemical and genetic testing is inconclusive. Considering rare causes-such as NR0B1 pathogenic variants in men-can be crucial for establishing a definitive diagnosis, with significant implications for the management of patients and their families.

This study analyzed five essential oils derived from plants that, despite sharing the common "pepper", belong to distinct genera and botanical families, which are increasingly recognized for their multifunctional bioactivities, including antioxidant, neuroprotective, and antimicrobial properties. In particular, five commercially available essential oils obtained from Pimenta dioica, Piper nigrum, Schinus molle, Schinus terebinthifolia, and Zanthoxylum armatum were chemically characterized and systematically evaluated for their biological potential. Gas chromatography-mass spectrometry analysis revealed distinct phytochemical profiles dominated by phenylpropanoids, monoterpenes, or oxygenated monoterpenes, which were further discriminated by multivariate statistical analysis. The essential oils were assessed in vitro for antioxidant capacity (DPPH and TEAC assays), anti-arthritic activity (protein denaturation inhibition), neuroprotective effects (acetylcholinesterase, butyrylcholinesterase, and tyrosinase inhibition), and antibiofilm activity against clinically relevant Gram-positive and Gram-negative bacteria. All oils exhibited measurable antioxidant and enzyme inhibitory activities, with P. dioica and P. nigrum showing the most balanced redox and neuroprotective profiles. Significant antibiofilm effects were observed during biofilm formation, while mature biofilms displayed strain- and oil-dependent susceptibility, highlighting differences between biomass reduction and metabolic inhibition. Overall, the results demonstrate that pepper-derived essential oils possess complementary and multi-target bioactivities strongly linked to their chemical composition, supporting their potential application as natural agents in food, pharmaceutical, and biomedical fields.

Patients with end-stage renal disease (ESRD) undergoing chronic hemodialysis (HD) frequently report the sensation of prostration, tiredness, weakness, exhaustion, weariness, or fatigue after the hemodialysis treatment. This condition is defined as post-dialysis fatigue and significantly impairs patients' ability to perform routine daily activities. The present study aims to investigate whether territorial or environmental factors such as differences in geographic areas are associated with the prevalence and characteristics of post-dialysis fatigue and time to recovery after dialysis among chronic HD patients. A total of 465 patients from six Italian HD units, located in both northern and central Italy, were enrolled between January and December 2024. Exclusion criteria included a dialysis duration of less than 1 year and a diagnosis of dementia, acute infectious disease, or active cancer. For each participant, demographic, clinical, and laboratory data were collected. The results showed that 61.5% of the patients reported suffering from post-dialysis fatigue. The prevalence and characteristics of post-dialysis fatigue, as well as the length of time to recovery after dialysis, varied significantly among the six HD units. Multivariate analyses revealed that the hemodialysis unit itself was the main variable significantly and independently associated with both post-dialysis fatigue and time to recovery after dialysis. Our findings suggest that environmental factors such as differences in geographic areas are associated with the prevalence and characteristics of post-dialysis fatigue and time to recovery after dialysis among chronic HD patients.

Genetic factors are key determinants in the pathophysiology of obesity, regulating energy homeostasis. Monogenic non-syndromic obesity accounts for 2-3% of obesity in both children and adults and is most often attributable to mutations in genes encoding components of the leptin-melanocortin pathway. Genetic testing is indicated in children with severe obesity before age 5, hyperphagia, a family history of obesity, and neurodevelopmental delay or organ dysfunction. Mutations associated with monogenic obesity follow autosomal recessive (LEP, LEPR, POMC, and PCSK1) or autosomal dominant (MC4R, SH2B1, SIM1, GNAS) modes of inheritance. Other gene mutations in heterozygous states (MRAP2, MC3R, SRC1, KSR2) are associated with obesity and may exhibit autosomal dominant inheritance; however, the clinical phenotype depends on the degree of genetic penetrance and interactions with other genetic and/or environmental factors. No approved targeted pharmacotherapies are currently available for autosomal dominant monogenic obesity, and the frequent detection of variants of uncertain significance often hinders timely diagnostic confirmation. The review provides a comprehensive appraisal of autosomal dominant forms of monogenic non-syndromic obesity, analyzing genetic and molecular features, clinical presentations, and therapeutic strategies.

Strong evidence links Epstein-Barr virus (EBV) infection to Multiple Sclerosis (MS). Peginterferon beta-1a (peg-IFN), currently the most used interferon formulation among first-line treatments in MS, displays immunomodulatory, anti-inflammatory, and antiviral properties and remains also an important therapeutic option in conditions such as pregnancy, lactation and aging patients. In this study we evaluated the ability of peg-IFN to restore a homeostatic EBV-host interaction in MS by regulating antiviral and immunometabolic responses. In people with MS (pwMS), peripheral blood mononuclear cells (PBMCs) were analyzed before (T0) and after six months (T6mos) of peg-IFN administration: IFN-stimulated gene (ISG) levels, EBV DNA load, Epstein-Barr nuclear antigen 2 (EBNA2) allele distribution, and T-lymphocyte phenotyping with glycolytic metabolism were assessed. Peg-IFN increased ISG transcription and glycolysis in CD4+ T lymphocytes, and reduced EBV DNA load without altering EBNA2 allele distribution. Notably, ISG expression increase at T6mos in pwMS infected by the non-risk 1.3B EBNA2 allele, correlating with a better long-term response to peg-IFN after 2-years. Lower T-cell glycolytic capacity at T0 predicted higher peg-IFN responsiveness in pwMS carrying the 1.3B allele, suggesting that EBNA2 variants might be predictive of response to peg-IFN. Here, we found that infection with MS-associated EBNA2 variants might be involved in the clinical response to peg-IFN therapy. The predictive model developed, which integrates immunological and viral parameters, may help clinicians in a finer selection of first-line therapies tailored to patient profiles, supporting personalized medicine approaches.

Since the onset of the COVID-19 pandemic, the World Health Organization has recommended vaccination for people with multiple sclerosis (pwMS). However, vaccine-induced immune responses in pwMS receiving immunomodulatory therapies are currently poorly characterized. Herein, we evaluated humoral and T cell-mediated immune responses against BNT162b2 mRNA vaccine in pwMS treated with cladribine (n = 30), focusing on how the time interval between drug administration and vaccination affects the magnitude and dynamics of vaccine-induced immune response. We found that cladribine influenced both B and T cell frequencies with different kinetics over time. Accordingly, vaccination after cladribine administration resulted in reduced antibody production but preserved T cell responses, whereas pwMS receiving vaccine before cladribine exhibited an effective humoral immunity but hampered SARS-CoV-2 Spike-specific T cell response. Our findings may inform the clinical decision-making process by providing evidence to support the identification of an appropriate time window for vaccination during cladribine treatment.

Claudin-3, Claudin-4, and Claudin-7 are expressed on the surface of epithelial cells. Their absence in neoplastic cells of epithelial origin is an aggressiveness marker in different cancers. The NF-YA gene codes for the Nuclear-Transcription-Factor-Y-Subunit-A, which is overexpressed in various tumors. In tumors, the relative ratio of the two major NF-YA alternative splicing isoforms, NF-YA long and NF-YA short, is associated with a mesenchymal phenotype and a poor prognosis. Based on a high NF-YA long/NF-YA short ratio, we generated a 158-gene signature that is common to Claudinlow Breast Carcinomas (BRCA) and Stomach Adenocarcinomas (STAD). To better classify STAD Claudinlow tumors, we employed a hierarchical clustering approach based on our 158-gene signature to classify STAD into a Claudinlow subgroup. We tested the classification potential of our signature in TCGA as well as in two additional datasets of tumors. We used the deep-learning DeepCC tool and the 158-gene signature to classify the STAD cell lines available in the CCLE platform. Obtained data were validated with qRT-PCR and Western blots. The 158-gene signature resulted in the selection of a STAD subgroup with effective Claudinlow expression and with a high NF-YA long/NF-YA short ratio. This Claudinlow subgroup was separated from the EMT subgroup of STAD and it is characterized by poor clinical outcome. We identified nine Claudinlow STAD cell lines with a high NF-YA long/NF-Y short ratio and validated the expression of selected markers. Our work supports the notion that three overlapping features-low expression of Claudin-3/4/7, high NF-YA long/NF-YA short ratio and a 158-gene signature-mark a specific subset of STAD characterized by mesenchymal features and poor prognosis.

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Background: Thyrotropin (TSH), even in the normal range, is associated with components of cardiometabolic syndrome. We aimed to assess the relation between TSH and cardiovascular (CV) risk in euthyroid patients with overweight/obesity without previous cardiac events. Methods: A total of 1588 subjects (1132 females, mean age 53 &#xb1; 14 years) were recruited. This was an observational study. TSH, body mass index, waist circumference (WC), creatinine, hepatic enzymes, homocysteine, C reactive protein, glycated hemoglobin, homeostatic model assessment for insulin resistance (HOMA-IR), basal and 2 h glucose and insulin, fibrinogen, uric acid, a complete blood count, a complete lipid profile, and blood pressure were measured in all subjects. The Atherosclerotic Cardiovascular Disease (ASCVD) risk score was calculated. Results: More severe degrees of obesity were associated with higher TSH quartiles; specifically, 33% of subjects with grade III obesity had TSH in the 75th percentile. Multiple regression showed that female gender (t-value 3.6, p < 0.001), HOMA-IR (1.9, &#x2264;0.05) and aspartate transaminase (AST; 2.8, <0.01) represent independent determinant factors affecting TSH levels in the population at higher CV risk (intermediate-high ASCVD risk score > 7.5%; n = 709). Similarly, TSH determinants in subjects with central obesity (n = 1197, WC >102 cm males, >88 cm females) were female gender (2.2, <0.05), HOMA-IR (2.7, <0.01) and smoking habit (-2.3, <0.5). Moreover, there was no significant relationship between TSH and ASCVD risk score. Conclusions: Higher TSH levels in the euthyroid range are related to high degrees of obesity and some CV risk factors, in subjects at higher cardiometabolic risk; however, for the different weight and sign of CV determinants (e.g., smoking habit) on the TSH system, the ASCVD risk score cannot evidence this relationship.