Biology subjects

Parisi, S.

Publications and source records attributed to Parisi, S..

3 recordsLinked to original sources

bioRxiv2026

Albumin-coated VS1 nanocrystals enable STARD3 inhibition and potentiate fluoropyrimidine therapy in colorectal cancer

Poor aqueous solubility remains a major obstacle to the translational development of targeted anticancer compounds. VS1, a first-in-class inhibitor of the cholesterol-transfer protein STARD3, has emerged as a promising chemosensitizing agent in colorectal cancer (CRC), but its clinical applicability is limited by its poor water solubility. Here, we combine structural biology, nanotechnology, and functional pharmacology to establish STARD3 inhibition as a delivery-enabled strategy to potentiate fluoropyrimidine therapy. To define the molecular basis of STARD3 inhibition, we solved the crystal structure of VS1 bound to the STARD3 ligand-binding domain at 2.1 [A] resolution, revealing direct occupation of the sterol-binding cavity. Molecular dynamics simulations confirmed a stable binding mode and identified the {Omega}1 loop as a dynamic gate regulating ligand binding and dissociation. To overcome the formulation barrier of VS1, we engineered carrier-free, albumin-coated nanocrystals through sonication-assisted nanocrystallization followed by surfactant exchange with human serum albumin. The resulting rod-shaped nanocrystals displayed nanometric size, narrow size distribution, sustained release, and improved aqueous dispersibility, increasing the apparent solubility of VS1 by more than 14-fold while preserving its molecular integrity and crystallinity. Biologically, VS1 selectively potentiated 5-fluorouracil (5-FU) in CRC cells, with synergistic effects restricted to 5-FU-sensitive models and associated with enhanced reactive oxygen species accumulation. Albumin-coated formulation retained the chemosensitizing activity of the free compound. In HCT-116 xenografts, combined treatment with albumin-coated VS1 nanocrystals and 5-FU significantly reduced tumor growth, prolonged tumor doubling time, and increased intratumoral necrosis without exacerbating systemic toxicity. Together, these findings establish that albumin-coated nanocrystals can overcome the delivery limitations of an insoluble STARD3 inhibitor and provide a formulation-enabled strategy to enhance fluoropyrimidine therapy in colorectal cancer. HIGHLIGHTSO_LIA 2.1 [A] crystal structure shows VS1 in the STARD3 sterol-binding cavity C_LIO_LIAlbumin-coated nanocrystals make the insoluble STARD3 inhibitor VS1 deliverable C_LIO_LINanocrystallization raises VS1 apparent solubility >14-fold with sustained release C_LIO_LIVS1 synergizes with 5-FU selectively in 5-FU-sensitive colorectal cancer lines C_LIO_LIAlbumin-nanocrystal VS1 plus 5-FU curbs xenograft growth without added toxicity C_LI

cancer biology↗

bioRxiv2026

Motor Neuron Dysfunction in SORD Deficiency: Implications for Therapeutic Development in Peripheral Neuropathies

Biallelic mutations in the sorbitol dehydrogenase (SORD) gene have been identified as one of the most common causes of autosomal-recessive Charcot-Marie-Tooth disease type 2 (CMT2) and distal hereditary neuropathy, collectively referred to as SORD deficiency. These mutations result in loss of sorbitol dehydrogenase activity, a key enzyme in the polyol pathway that metabolizes glucose, leading to marked accumulation of sorbitol in patient-derived fibroblasts. However, the mechanisms by which SORD dysfunction drives axonal degeneration remain poorly understood, and robust in vitro models of human SORD-deficient motor neurons (MNs) are still lacking. To address this gap, we established a human in vitro model of SORD deficiency by generating induced pluripotent stem cells (iPSCs) from fibroblasts affected individual carrying biallelic SORD mutations (SORDc.757delG/c.316_425+165del), and unaffected heterozygous carriers (SORDc.757delG/wt and SORDwt/c.316_425+165del). These iPSCs were subsequently differentiated into motor neuron progenitors (MNPs) and MNs. Comprehensive analysis of SORD-deficient human cells--including fibroblasts, MNPs, and MNs--revealed pronounced structural and functional abnormalities in the mitochondrial compartment, characterized by mitochondrial fragmentation and increased proton leak. Importantly, fibroblasts derived from two additional unrelated patients carrying the SORD mutation (SORDc.757delG/ c.757delG) further confirmed that SORD deficiency is associated with a mitochondrial phenotype. At the molecular level, SORD deficiency led to upregulation of aldose reductase (AR), another key enzyme of the polyol pathway, resulting in disruption of cellular redox homeostasis and increased oxidative stress. Consistent with these alterations, MNs derived from CMT2/SORD patients exhibited clear neurodegenerative features, including severe defects in neurite branching and synaptic architecture, ultimately impairing neuronal connectivity. Notably, pharmacological inhibition of AR effectively rescued both mitochondrial dysfunction and neuronal structural defects, supporting the targeting of AR as a promising therapeutic strategy for polyol pathway-associated neuropathies as CMT2/SORD and diabetic neuropathy.

cell biology↗

bioRxiv2024

The RNA binding protein LIN28A mediates chromatin dynamics during neuronal differentiation

The transition of embryonic stem cells (ESCs) from pluripotency to lineage commitment is regulated by multiple mechanisms, including chromatin dynamics and both transcriptional and post-transcriptional processes. Recent advances have highlighted that these mechanisms often interact, forming intricate multi-layered regulatory networks that require detailed characterization. In this study, we demonstrate that the RNA-binding protein LIN28A plays a pivotal role in neuronal differentiation by mediating RNA-dependent interactions with the Polycomb repressive complex 2 (PRC2). This interaction facilitates the eviction of PRC2 from chromatin, thereby activating a neuronal lineage-specific transcriptional program. Proteomic analyses revealed that the LIN28A interactome undergoes substantial remodeling during differentiation, corresponding to changes in LIN28A localization. In ESCs, LIN28A is predominantly nuclear and interacts with several components of the PRC2 complex in an RNA-dependent manner, assisting in chromatin dynamics. Our findings show that in the absence of LIN28A, PRC2 remains associated with chromatin, impairing the expression of genes critical for neuronal differentiation in ESCs. Chromatin immunoprecipitation sequencing (ChIP-seq) further confirmed that loss of LIN28A results in preferential PRC2 occupancy at the promoters of differentiation-associated genes. This study uncovers a novel role for LIN28A in epigenetic remodeling, which is essential for the proper differentiation of ESCs into the neuronal lineage.

molecular biology↗