Lorenzo Franci

Background: Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) is a global health priority affecting approximately 30% of the population. It represents the hepatic manifestation of metabolic syndrome, potentially progressing from simple steatosis to Metabolic Dysfunction-Associated Steatohepatitis (MASH), cirrhosis, and hepatocellular carcinoma. This review aims to compare current knowledge of MASLD in mouse models and humans, focusing on pathophysiology, histological phenotypes, and the role of preclinical imaging as a non-invasive translational screening tool. Methods: A literature search was conducted in PubMed and Web of Science to identify English-language publications from January 2020 to March 2026 on murine models and imaging techniques for MASLD, using pertinent keywords. Attention was given to highlighting similarities and differences between human and murine approaches. Results: MASLD arises from complex interactions between genetics, sedentary lifestyles, and imbalanced diets. While mouse models have been refined to capture the multifactorial interplay driving disease progression and are still essential for drug development, no single model fully mirrors the human condition. Histological assessment remains an essential tool for MASLD staging, in both humans and mouse models. However, imaging is increasingly emerging as an important complementary technique to non-invasively investigate MASLD. Conclusions: Mouse models are essential to address specific mechanistic and therapeutic questions, but understanding of their limitations and strengths is crucial for translational research. Integrating phenotype-driven approaches in both humans and mice, combining traditional histology, quantitative imaging, and metabolic profiling, as well as longitudinal, combined, and humanized preclinical models, will enhance translational alignment and accelerate the development of therapies for MASLD.

Background Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) is a global health priority affecting approximately 30% of the population. It represents the hepatic manifestation of metabolic syndrome, potentially progressing from simple ste-atosis to Metabolic Dysfunction-Associated Steatohepatitis (MASH), cirrhosis, and hepa-tocellular carcinoma. This review aims to compare current knowledge of MASLD in mouse models and humans, focusing on pathophysiology, histological phenotypes, and the role of preclinical imaging as a non-invasive translational screening tool. Methods The study synthesizes recent evidence (last five years) regarding the multi-factorial aetiology of MASLD, focusing on some of the key aspects in selecting the ap-propriate animal model and on the recent non-invasive techniques applicable to both humans and mice. Results MASLD arises from complex interactions between genetics, sedentary lifestyles, and imbalanced diets. While mouse models have been refined to capture the multifac-torial interplay driving disease progression and are still essential for drug development, no single model fully mirrors the human condition. This process must take into account key variables, including diet composition, mouse strain, the use of genetically modified mice (GEMs), and housing temperature. Histological assessment remains the gold standard for MASLD staging, particularly in mouse models; however, preclinical im-aging is increasingly emerging as a complementary, non-invasive technique for in vivo investigation. Conclusions Rational, fit-for-purpose mouse models are essential to address specific mechanistic and therapeutic questions. Given the multifactorial and heterogeneous na-ture of MASLD, understanding the limitations and strengths of specific mouse models is therefore crucial for translational research. Integrating phenotype-driven approaches in both humans and mice, combining traditional histology, quantitative imaging and metabolic profiling, as well as longitudinal, combinatorial and humanized preclinical models, will enhance translational alignment and accelerate the development of therapies for MASLD.

Background: Accumulation of lipids in the liver characterizes metabolic dysfunction–associated steatotic liver disease (MASLD), the most prevalent chronic liver disease worldwide. Methods: To explore the role of mitogen-activated protein kinase 15 (MAPK15) in mammalian lipid homeostasis, we created and characterized the first knockout mouse model for this gene. Hepatocellular in vitro models were also used to further investigate molecular mechanisms underlying MAPK15-dependent regulation of lipid metabolism in the liver. Results: We observed that Mapk15-/- mice exhibited liver steatosis in the context of a MASLD-like phenotype while hepatocellular in vitro models allowed to demonstrate that dysregulated accumulation of lipids was due to increased expression and membrane localization of the CD36 fatty acid translocase. Consistently, Mapk15-/- mice exhibited elevated hepatic levels of CD36 and feeding them with a western-type diet significantly accelerated their progression to a steatohepatitis-like phenotype. Importantly, transcriptomic analysis of human cohorts revealed increased liver expression of MAPK15 in MASLD patients, suggesting a compensatory role in disease progression. In this context, overexpression of this kinase efficiently opposed lipid accumulation in a MASLD hepatocellular model, opening to the possibility of counteracting hepatic steatosis in humans by pharmacologically or genetically activating this MAP kinase. Conclusions: Presented data highlight a critical role for MAPK15 in liver physiopathology, by contributing to maintaining physiological intracellular levels of lipids in this tissue.

Cell-based drug delivery has emerged as a powerful strategy to improve therapeutic targeting while reducing systemic toxicity. This approach is particularly valuable for anticancer agents, which are often limited by severe side effects arising from off-target activity and non-specific distribution. By using cells as carriers, drugs can evade immune clearance, achieve prolonged circulation, and improve pharmacokinetic profiles, ultimately enhancing therapeutic efficacy. This review surveys the current landscape of cell-mediated drug delivery in oncology, emphasizing both fundamental principles and practical applications. We discuss the design and preparation of cellular carriers, examine the unique characteristics of commonly used cell types, and highlight recent technological innovations that are expanding their theranostic potential, focusing on strategies for delivery to challenging anatomical sites, with a dedicated focus on the brain. By consolidating recent advances and insights, this review aims to provide a comprehensive perspective on the promise and future directions of cell-based drug delivery for cancer therapy.

Cell-based drug delivery has emerged as a powerful strategy to improve therapeutic targeting while reducing systemic toxicity. This approach is particularly valuable for anticancer agents, which are often limited by severe side effects arising from off-target activity and non-specific distribution. By using cells as carriers, drugs can evade immune clearance, achieve prolonged circulation, and improve pharmacokinetic profiles, ultimately enhancing therapeutic efficacy. This review surveys the current landscape of cell-mediated drug delivery in oncology, emphasizing both fundamental principles and practical applications. We discuss the design and preparation of cellular carriers, examine the unique characteristics of commonly used cell types, and highlight recent technological innovations that are expanding their theranostic potential, focusing on strategies for delivery to challenging anatomical sites, with a dedicated focus on the brain. By consolidating recent advances and insights, this review aims to provide a comprehensive perspective on the promise and future directions of cell-based drug delivery for cancer therapy.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is one of the most common chronic liver disorders worldwide and can lead to inflammation, fibrosis, and liver cancer. To better understand the impact of an unbalanced hypercaloric diet on liver phenotype in impaired autophagy, the study compared C57BL/6J wild type (WT) and MAPK15-ERK8 knockout (KO) male mice with C57BL/6J background fed for 17 weeks with “Western-type” (WD) or standard diet (SD). Liver features were monitored in vivo by high-frequency ultrasound (HFUS) using a semi-quantitative and parametric assessment of pathological changes in the parenchyma complemented by computer-aided diagnosis (CAD) methods. Liver histology was considered the reference standard. WD induced liver steatosis in both genotypes, although KO mice showed more pronounced dietary effects than WT mice. Overall, HFUS reliably detected steatosis-related parenchymal changes over time in the two mouse genotypes examined, consistent with histology. Furthermore, this study demonstrated the feasibility of extracting quantitative features from conventional B-mode ultrasound images of the liver in murine models at early clinical stages of MASLD using a computationally efficient and vendor-independent CAD method. This approach may contribute to the non-invasive characterization of genetically engineered mouse models of MASLD according to the principles of replacement, reduction, and refinement (3Rs), with interesting translational implications.

Human type I interferons are crucial regulators of immune responses, essential for controlling infections and activating immune cells. Among them, Interferon Beta (IFNB1) plays a key role in inflammation, and its dysregulation is linked to various diseases, driving efforts to understand the molecular events governing its expression. Here, we identified Mitogen-Activated Protein Kinase 15 (MAPK15) as a novel regulator of IFNB1. Using luciferase reporter assays, gene expression analysis and Enzyme-Linked Immunosorbent Assay (ELISA), we found that MAPK15 downregulation enhanced IFNB1 and Interferon-Stimulated Genes expression and increased IFNB1 secretion. To unveil the underlying mechanisms, we investigated the transcription factors acting on the IFNB1 promoter, revealing that MAPK15 downregulation induced JUN activation. Importantly, pharmacological inhibition of c-Jun N-terminal Kinases (JNKs) supported a key role for this enzyme in JUN activation and consequent IFNB1 expression. Ultimately, by using the antioxidant N-acetylcysteine ethyl ester (NACET), we demonstrated that oxidative stress, induced by MAPK15 downregulation, was responsible for JUN activation and IFNB1 expression. Overall, our findings unveil a novel mechanism by which MAPK15 modulates IFNB1 expression, positioning this kinase as a pivotal regulator of this gene. This insight opens promising avenues for therapeutic intervention, as targeting MAPK15 activity could offer a strategy to rebalance cytokine expression in chronic inflammatory diseases characterized by immune dysregulation.

Accumulation of lipids in the liver characterizes metabolic dysfunction-associated steatotic liver disease (MASLD), the most prevalent chronic liver disease worldwide. As liver injury progresses to metabolic dysfunction-associated steatohepatitis (MASH), MASLD can predispose individuals to cirrhosis and hepatocellular carcinoma. Here, we characterized the first knockout mouse model for mitogen-activated protein kinase 15 (MAPK15) and revealed its critical role in controlling lipid homeostasis in the liver. Indeed, Mapk15 ^-/- mice exhibited a MASLD-like phenotype, and hepatocellular models allowed us to demonstrate that dysregulated accumulation of lipids was due to increased expression and membrane localization of the CD36 fatty acid translocase. Consistently, Mapk15 ^-/- mice exhibited elevated hepatic levels of CD36 and feeding them with a western-type diet significantly accelerated their progression to a MASH-like phenotype. Ultimately, transcriptomic analysis of human cohorts revealed increased liver expression of MAPK15 in MASLD patients, compared to unaffected individuals, ultimately supporting a protective role for MAPK15 against this disease. Overall, our data highlight a critical role for MAPK15 in liver physiopathology, by contributing to maintain physiological intracellular levels of lipids in this tissue.

Triple-negative breast cancer (TNBC) is a very aggressive and heterogeneous group of tumors. In order to develop effective therapeutic strategies, it is therefore essential to identify the subtype-specific molecular mechanisms underlying disease progression and resistance to chemotherapy. TNBC cells are highly dependent on exogenous cystine, provided by overexpression of the cystine/glutamate antiporter SLC7A11/xCT, to fuel glutathione synthesis and promote an oxidative stress response consistent with their high metabolic demands. Here we show that TNBC cells of the mesenchymal stem-like subtype (MSL) utilize forced cystine uptake to induce activation of the transcription factor NRF2 and promote a glutathione-independent mechanism to defend against oxidative stress. Mechanistically, we demonstrate that NRF2 activation is mediated by direct cysteinylation of the inhibitor KEAP1. Furthermore, we show that cystine-mediated NRF2 activation induces the expression of important genes involved in oxidative stress response, but also in epithelial-to-mesenchymal transition and stem-like phenotype. Remarkably, in survival analysis, four upregulated genes (OSGIN1, RGS17, SRXN1, AKR1B10) are negative prognostic markers for TNBC. Finally, expression of exogenous OSGIN1, similarly to expression of exogenous NRF2, can prevent cystine depletion-dependent death of MSL TNBC cells. The results suggest that the cystine/NRF2/OSGIN1 axis is a potential target for effective treatment of MSL TNBCs.