Beyond readthrough: ataluren restores mitochondrial function and reduces oxidative stress in FANCA-mutated cells via mTOR–DRP1 modulation Matilde Balbi, Elisa Guidi, Anca Manuela Hristodor, Fabio Corsolini, Vanessa Cossu, et al. Cell Death Discovery, 2026 Fanconi anemia (FA) is a rare inherited bone marrow failure syndrome characterized by genomic instability, mitochondrial dysfunction, and oxidative stress. While the therapeutic potential of ataluren, a translational readthrough-inducing drug, has been investigated in FA cells carrying nonsense mutations, its broader metabolic impact remains unclear. Here, we demonstrate that ataluren (tested at 2.5, 5, and 10 μM) modulates cellular energy metabolism and redox homeostasis in FA lymphoblasts harboring either nonsense or missense mutations in the FANCA gene. At low doses (2.5 μM for 72 h), ataluren improved the ATP/AMP ratio, enhanced oxidative phosphorylation efficiency, and reduced lipid peroxidation and oxidative DNA damage. These effects were independent of mutation type and were not associated with compensatory glycolysis, as lactate dehydrogenase activity remained unchanged. Strikingly, ataluren restored the P/O ratio under pyruvate/malate-driven respiration to near-normal values, indicating improved coupling between oxygen consumption and ATP synthesis. Mechanistically, ataluren reduced DRP1 protein levels and attenuated mTOR-S6 signaling, suggesting that mitochondrial dynamics and bioenergetic efficiency are modulated via the mTOR–DRP1 axis. Additionally, ataluren lowered IMPDH activity, contributing to reduced cell proliferation and DNA damage without impairing cellular energy status. Notably, these beneficial effects persisted under immune stimulation, where ataluren mitigated the metabolic and oxidative burden imposed by lymphocyte activation. Our findings unveil a pleiotropic role for ataluren that extends beyond its canonical readthrough activity, highlighting its potential as a metabolic modulator for FA and possibly other DNA repair–deficient disorders.
Exploring the impact of age, sex and life experiences on plasma inflammatory profiles through comparative proteomics Martina Bartolucci, Olga Utyro, Anita Muraglia, Alessia Repetto, Vanessa Agostini, et al. Frontiers in Immunology, 2026 Background In the heterochronic parabiosis model it has been shown that blood from elderly animals exhibits markedly reduced rejuvenating effects compared to that of young organisms. Furthermore, human plasma from older subjects, when used as a supplement in cell culture media, is significantly less effective than plasma derived from younger individuals. This study analyzed plasma from a cohort of 229 subjects by a proteomic approach to reveal age-related changes. Methods A mass spectrometry-based proteomic analysis was performed on plasma samples from 3 age-groups: a prepubertal, a healthy young adult group and a cohort of individuals over 75 years old with three different life-experiences. An additional parallel study was conducted by a Milliplex Luminex assay. Results The proteomic analysis revealed a chronic inflammatory state in the elderly population, along with complement activation and impaired regulation of blood coagulation. This inflammatory condition was confirmed by Luminex assay, showing elevated levels of classical pro-inflammatory cytokines in the plasma of elderly individuals. Moreover, the elderly group showed a reduced production of antibody light chains, suggesting concurrent immunosenescence. In the older group we identified 25 upregulated proteins whose elevated abundance, combined with acquired immune aging may constitute a plasma proteomic signature of aging. The degree of upregulation of these signature proteins varied among elderly subgroups with different life-experience. A good physical condition and/or cognitive function correlated with a lower expression of the aging-related proteomic profile. Furthermore, several sex-specific differences were identified in the plasma profiles of young donors. Reversely, among elderly individuals, no major differences were observed, except for an increased level of Pregnancy Zone Protein (PZP) in females. Conclusions Proteomic analysis of plasma revealed protein variations associated with aging, primarily involving inflammation-related pathways, immunosenescence features, and sex-linked differences. This study highlights the pathological characteristics underlying the aging process.
Dysregulated cortical excitability and tau phosphorylation in a β3 integrin mouse model of autism Carmela Vitale, Fanny Jaudon, Rafael Luján, Martina Bartolucci, Lucia Celora, et al. Brain, 2025 Autism spectrum disorder is a complex neurodevelopmental disease characterized by altered cortical network excitability. Recent genetic studies have identified deep layer V cortical pyramidal neurons in the frontal cortex as central to autism pathophysiology, yet the cortical circuits, plasticity mechanisms and molecular signalling pathways involved remain poorly understood. Layer V pyramidal neurons consist of two main types with distinct functional roles: intratelencephalic neurons, which respond to low-frequency stimulation and project within the cortex and striatum, and pyramidal tract neurons, which are tuned to theta-frequency inputs and convey information to subcortical structures. Determining which of these two neuron types is more critical to autism pathophysiology and whether disruptions in their synaptic connectivity or intrinsic excitability contribute to autism-related dysfunctions would significantly advance our understanding of the disorder. Integrins, a family of cell adhesion molecules, are vital for neuronal function. The gene encoding β3 integrin (ITGB3) is genetically linked to autism spectrum disorder, with rare mutations identified in affected individuals, while Itgb3 knockout mice exhibit autism-like behaviours, including impaired social memory and increased grooming. However, it remains unclear why loss of β3 integrin is associated with autism spectrum disorder, how it disrupts cortical circuits, and which plasticity mechanisms and molecular pathways are involved. Here, we demonstrate that β3 integrin selectively regulates the excitability of pyramidal tract neurons in the medial prefrontal cortex. Using electrophysiology, proteomics and molecular approaches, we show that β3 integrin regulates the gain, adaptation and precision of action potential discharge by controlling the surface expression of Ca2+-activated SK2 channels. Genetic ablation of Itgb3 impaired intrinsic excitability and SK2 channel function in pyramidal tract neurons, with no effects in intratelencephalic neurons. Furthermore, we identified Tau, a protein traditionally linked to neurodegenerative diseases, as part of the SK2 channel interactome. Proteomic analyses revealed altered protein kinase A-dependent phosphorylation of Tau in Itgb3 knockout mice, while protein kinase A inhibition restored SK2 channel currents, thereby connecting phosphorylation changes to excitability deficits. Our findings expand the current mechanistic framework linking signalling pathway dysfunctions to cortical excitability deficits, highlighting the dysregulation of pyramidal tract neuron excitability as a core feature of autism pathophysiology and demonstrating the involvement of β3 integrin, SK2 channels, Tau and PKA in this process. Because pyramidal tract neurons serve as final integrators of cortical computations before relaying information outside the cortex, their impaired excitability may disrupt communication with subcortical targets, contributing to the complex pathophysiology of autism spectrum disorder.
Evaluation of the Effects of Sumac (Rhus coriaria) Extract-Loaded Ethosomes on an In Vitro Wound Healing Model Melis Emanet, Matteo Battaglini, Alessio Carmignani, Federico Catalano, Martina Bartolucci, et al. ACS Omega, 2025 Wound healing involves a series of complex bioprocesses, including repairing skin damage, maintaining its barrier features, and preserving all other skin functions. Since the skin is the primary organ exposed to external factors, these bioprocesses can be interrupted by potential exogenous toxicants. Efforts to mitigate the effects of these toxicants can help accelerate the healing process, facilitating complete wound recovery. In this context, sumac () extract, rich in polyphenolics with antioxidant and anti-inflammatory properties, can be exploited to overcome oxidant and inflammation-dependent burdens. Ethosomes, lipid-based intradermal delivery vehicles, have been selected for the delivery of sumac extract, as they enhance penetration through the skin layers. Considering their remarkable flexibility and deformability, ethosomes can minimize drug leakage even under harmful penetration conditions. Given the diverse bioactive content of sumac extract, ethosomes have been considered ideal for delivering both hydrophilic and lipophilic active compounds. Sumac extract (SuExt)-loaded ethosomes (SuExt-ethosomes) were therefore produced and characterized. These nanocarriers demonstrated significant cellular internalization and cytocompatibility in human dermal fibroblasts (HDFs), along with excellent antioxidant and anti-inflammatory activity. A comprehensive investigation, supported by proteomic analysis, revealed that SuExt-ethosomes present promising wound healing potential, supporting future investigations in preclinical models.
Two-photon polymerization of miniaturized 3D scaffolds optimized for studies on glioblastoma multiforme in spaceflight-like microgravity conditions Giada Graziana Genchi, Claudio Conci, Özlem Şen, Alessandra Nardini, Martina Bartolucci, et al. Biofabrication, 2025 The obtainment of innovative models recalling complex tumour architectures and activities in vitro is a challenging drive in the understanding of pathology molecular bases, yet it is a crucial path to the identification of targets for advanced oncotherapy. Cell environment recapitulation by 3D scaffolding and gravitational unloading of cell cultures represent powerful means in tumour biomimicry processes, but their simultaneous adoption has consistently been explored only in the latest decade. Here, an unprecedented bioengineering approach capitalizing on spaceflight biology practice is proposed for modelling of glioblastoma multiforme, a highly aggressive neoplasm that affects the central nervous system and has poorly effective pharmacological and radiological countermeasures. Tumour modelling was pursued by the original implementation of two-photon polymerization in fast prototyping of 3D scaffolds on flexible substrates for U87-MG glioma cell culture, and by the exposure of cell-laden scaffolds to simulated microgravity (s-μg). Realistic spaceflight conditions were applied to collect preliminary information suitable for testing of U87-MG cell-laden scaffold in low Earth orbit. Responses of glioma cells anchored to 3D scaffolds were investigated by microscopy, quantitative reverse transcription-polymerase chain reaction and proteomic analyses, revealing synergic regulatory effects of cell scaffolding and s-μg on markers of tumour cell growth, metabolism and invasiveness.
