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The Notch signaling pathway, a vital and evolutionarily conserved regulator of cellular processes, intricately shapes both health and disease. In the realm of health, Notch signaling assumes a pivotal role in the skin homeostasis, orchestrating primary growth arrest and progressive keratinocyte differentiation processes [1]. Moreover, Notch signaling is also critical in other adult organs and tissues such as the liver, intestine, hematopoietic system, and skeletal muscle. Its involvement in immune cell homeostasis and organ-specific immune responses accentuates its overarching significance in overall immune function [2]. Moreover, the pathway contributes to the integrity of the vasculature, the development of smooth muscle cells, and intricate processes such as osteogenic differentiation, highlighting its versatile role in maintaining physiological balance. Conversely, dysregulation of Notch signaling is implicated in an array of diseases. In cancer, aberrant Notch activation is intricately linked to tumor initiation, progression, and chemoresistance across various malignancies [3]. Cardiovascular disorders, exemplified by myocardial infarction, showcase the cardioprotective effects of Notch signaling [4], while neurological conditions like Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) underscore its role in hereditary strokes [5]. In essence, unraveling the nuanced dynamics of Notch signaling is paramount for understanding the molecular underpinnings of diseases and harnessing its therapeutic potential. The multifaceted involvement of Notch signaling in health and disease underscores its intricate nature, positioning it as a promising avenue for targeted interventions and personalized medicine.

Background/Aims: Mevalonate Kinase Deficiency (MKD), is a hereditary disease due to mutations in mevalonate kinase gene (MVK). MKD has heterogeneous clinical phenotypes: the correlation between MVK mutations and MKD clinical phenotype is still to be fully elucidated. Deficiency of prenylated proteins has been hypothesized as possible MKD pathogenic mechanism. Based on this hypothesis and considering that neurologic impairment characterizes Mevalonic Aciduria (MA), the most severe form of MKD, we studied the effects of I268T and N301T MVK mutations on protein prenylation, autophagy and programmed cell death in SH-SY5Y neuroblastoma cell lines. Methods: SH-SY5Y cells were transiently transfected, with the pCMV-6 plasmid containing MVK wild type and the two mutated sequences. Protein prenylation levels were evaluated using GFP-RhoA-F to assess farnesylation, and GFP-RhoA to evaluate geranylgeranylation; autophagy was measured by evaluating LC3 and p62 protein levels, while Annexin V-FITC and Propidium Iodide staining allowed apoptosis detection. Results: MVK mutants’ over-expression causes decreased levels of farnesylation and geranylgeranylation, and also increased LC3 lipidation in SH-SY5Y, with concomitant p62 accumulation. Treatment with bafilomycin A1 (an inhibitor of vacuolar H+-ATPase, a late autophagy inhibitor) further increase LC3-II and p62 levels, suggesting that degradation of autophagolysosome could be impaired. SH-SY5Y, with both MVK mutants, showed apoptosis increase; the presence of N301T associated with augmented cell death. Conclusions: We hypothesize that mevalonate pathway impairment causes alteration of farnesylation and geranylgeranylation proteins and alteration of the autophagic flux; these changes can induce apoptosis, possibly more relevant in the presence of N301T mutation.

Zika virus (ZIKV) still constitutes a public health concern, however, no vaccines or therapies are currently approved for treatment. A fundamental process involved in ZIKV infection is autophagy, a cellular catabolic pathway delivering cytoplasmic cargo to the lysosome for degradation—considered as a primordial form of innate immunity against invading microorganisms. ZIKV is thought to inhibit the Akt-mTOR signaling pathway, which causes aberrant activation of autophagy promoting viral replication and propagation. It is therefore appealing to study the role of autophagic molecular effectors during viral infection to identify potential targets for anti-ZIKV therapeutic intervention.

This work was supported by a Biomolecular Analyses for Tailored Medicine in AcneiNversa (BATMAN) project, funded by ERA PerMed (JTC_2018) to S.C.; by a Starting Grant (SG- 2019-12369421) funded by Italian Ministry of Health to P.M.T.; by two grants, from the Italian Ministry of University and Research (MUR) “Programmi di Ricerca Scientifica di Rilevante Interesse Nazionale 2017” (PRIN2017 # 2017J92TM5) and “Fondo Integrativo Speciale per la Ricerca 2020” (FISR 2020 CoVAPin # FISR2020IP_04051), to Giuseppe Calamita; and a grant from the University of Bari “Horizon Europe Seeds 2022-2023” (Uniba Euroseeds #S10) to Giuseppe Calamita.

ThisworkwassupportedbyaBiomolecularAnalysesforTailoredMedicineinAcneiNversa (BATMAN)project, funded by ERA PerMed (JTC_2018) to A.V.M and S.C. and by a Starting Grant (SG-2019-12369421) funded by the Italian Ministry of Health to P.M.T.

Hidradenitis suppurativa (HS) is a chronic, recurrent inflammatory skin disorder of the pilosebaceous unit, characterized by nodules, abscesses, and sinus tracts formation in apocrine gland-bearing skin. Increasing evidence suggests that HS is not solely a localized dermatological condition, but part of a broader systemic inflammatory state closely associated with metabolic dysfunction. Meta-inflammation, defined as a chronic, low-grade inflammatory response driven by metabolic imbalance, has emerged as a key mechanism linking obesity, insulin resistance, and immune dysregulation to the pathogenesis and progression of HS. It has indeed been demonstrated in numerous studies that HS and metabolic syndrome (MetS) share a core link through meta-inflammation, driven by common pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6. These pathways, along with insulin resistance and obesity-related adipose tissue dysfunction, drive both skin disease severity and metabolic comorbidities often creating a self-perpetuating cycle of inflammation and tissue damage. Understanding the interplay between meta-inflammation and HS provides important insights into disease heterogeneity and highlights the need for a multidisciplinary therapeutic approach. Targeting meta-inflammation through lifestyle interventions, weight management, and immuno-metabolic therapies may complement established treatments and improve clinical outcomes. In this review, we explore the pathogenic link between meta-inflammation and HS and discuss the therapeutic targets arising from this intricate interplay.

This work was supported by a Biomolecular Analyses for Tailored Medicine in AcneiNversa (BATMAN) project, funded by ERA PerMed and by a grant from the Institute for Maternal and Child Health IRCCS ‘Burlo Garofolo/Italian Ministry of Health’ (RC16/2018)

The challenge of unravelling the molecular basis of multifactorial disorders nowadays cannot rely just on association studies searching for potential causative variants shared by groups of patients and not present in healthy individuals; indeed, association studies have as a main limitation the lack of information on the interactions between the disease-causing variants. Thus, new genomic analysis tools focusing on disrupted pathways rather than associated gene variants are required to better understand the complexity of a disease. Therefore, we developed the Variant Enrichment Analysis (VEA) workflow, a tool applicable for whole exome sequencing data, able to find differences between the numbers of genetic variants in a given pathway in comparison with a reference dataset. In this study, we applied VEA to discover novel pathways altered in patients with complex autoinflammatory skin disorders, namely PASH (n = 9), 3 of whom are overlapping with SAPHO) and PAPASH (n = 3). With this approach we have been able to identify pathways related to neutrophil and endothelial cells homeostasis/activations, as disrupted in our patients. We hypothesized that unregulated neutrophil transendothelial migration could elicit increased neutrophil infiltration and tissue damage. Based on our findings, VEA, in our experimental dataset, allowed us to predict novel pathways impaired in subjects with autoinflammatory skin disorders.

Pyoderma gangrenosum (PG) is a rare inflammatory skin disease classified within the spectrum of neutrophilic dermatoses. The pathophysiology of PG is yet incompletely understood but a prominent role of genetics facilitating immune dysregulation has been proposed. This study investigated the potential contribution of disrupted molecular pathways in determining the susceptibility and clinical severity of PG. Variant Enrichment Analysis, a bioinformatic pipeline applicable for Whole Exome Sequencing data was performed in unrelated PG patients. Eleven patients were enrolled, including 5 with unilesional and 6 with multilesional PG. Fourteen pathways were exclusively enriched in the \"multilesional\" group, mainly related to immune system (i.e., type I interferon signaling pathway), cell metabolism and structural functions. In the \"unilesional\" group, nine pathways were found to be exclusively enriched, mostly related to cell signaling and cell metabolism. Genetically altered pathways involved in immune system biology and wound repair appear to be nodal pathogenic drivers in PG pathogenesis.

Hidradenitis suppurativa (HS) is a chronic autoinflammatory skin disorder with a complex genetic and molecular basis. To advance its characterization, we applied InterOmics, a novel bioinformatics pipeline integrating whole exome sequencing (WES) and RNA sequencing (RNA-seq), to saliva and skin biopsy samples from six HS patients. This approach enabled a comprehensive multiomics investigation, identifying disease-associated genetic variants and transcriptomic alterations. A key innovation of InterOmics is the Multiomics Variant Category, which classifies variants based on DNA and RNA data, capturing regulatory mechanisms such as allele-specific expression, RNA editing, nonsense-mediated decay, and gain-of-function mutations. Our findings highlight HLA gene variants and keratin-related mutations as potential contributors to HS pathogenesis. By bridging genomic and transcriptomic data, InterOmics enhances variant interpretation. This study underscores the power of multiomics-driven approaches in deciphering complex diseases, paving the way for precision medicine in HS.