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Background: Malignant mesothelioma (MM) is a rare and aggressive form of cancer that affects the mesothelial surfaces, associated with exposure to asbestos fibres. To date, no cure is available for MM and therapeutically approved treatments are based on the use of platinum compounds often used in combination with other drugs. We have previously analysed the efficacy of a cisplatin/piroxicam (CDDP/P) combined treatment showing that this treatment was able to reduce in vivo tumor growth. Several studies reported that platinum-drug sensitivity in cancer is connected to modulation of the expression of non-coding RNAs. In this study we analysed if the CDDP/P treatment was able to modulate miRNAs expression in MM., Methods: miRNA sequencing performed on MSTO-211 H cells treated with CDDP with CDDP/P led us to identify miRNA-503 - downregulated by CDDP/P - as a novel miRNA that acts as an oncomiR in MM. The effect of miRNA-503 inhibition was evaluated in vitro in mesothelioma cells analysing apoptosis induction and reduction of cancer properties. Inhibition of miR-503 expression in vivo, was analysed in ectopic mouse model of MM by using LNP encapsulating anti-mir-503 and miR-503 expression was evaluated in human MM samples., Results: In vitro and in vivo analysis confirmed miR-503 acts as oncogene in MM since its inhibition was able to reduce cell cancer properties and tumor growth in ectopic mouse model of MM. Its expression was found upregulated in human MM patients compared to normal pleura. Bioinformatic analysis indicated BTG1, CCNG1, EDG1, and TIMP2 as putative target genes of miRNA-503. These genes showed an opposite expression compared to miR-503 levels both in cells and in MM samples. Finally, microarray analysis indicated that miR-503 inhibition affected the expression of the well-known MM biomarkers: CXCL8, SERPINE1 and Osteopontin., Conclusions: Our study is the first reporting an oncomiR role for miR-503 in MM and suggests that its inactivation could have a clinical value in MM patients. This study reveals that miRNA-503 acts as an oncomiR in MM suggesting that its inhibition, through LNP delivery, has the potential to be considered as a novel therapeutic strategy in MM., Competing Interests: Declarations. Ethical approval and consent to participate: For human samples used in this study, each subject gave a written informed consent in accordance with Italian law. Samples were processed under approval of the written consent statement by Ethical Committee of AOU of the Second University of Naples, Italy and of the University Hospital of Marche, Italy respectively. The animal study was performed according to the European Community Council Directive 2010/63/EU, approved by the local Ethical Committee for Animal Experiments of the ENEA, and authorized by the Italian Ministry of Health (PR 415/2021 and extension EE25E.15.EXT.0). Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Deciphering the sources of variability in drug responses requires to understand the processes modulating drug pharmacokinetics. However, pharmacological research suffers from poor reproducibility across clinical, animal, and experimental models. Predictivity can be improved by using Organs-on-Chips, which are more physiological, human-oriented, micro-engineered devices that include microfluidics. OoC are particularly relevant at the fundamental and preclinical stages of drug development by providing more accurate assessment of key pharmacokinetic events. We have developed a proximal tubule-on-a-chip model combining commercial microfluidic and chip technologies. Using the RPTEC/TERT1 cell line, we set up a dual-flow system with antiparallel flows to mimic the dynamics of blood and urine. We assessed transporters mRNA expression, cellular polarization and protein expression via immunofluorescence, and monitored the transcellular transport of prototypic xenobiotics by determining their efflux ratios. Our results show that flow exposure significantly modulate mRNA expression of drug membrane transporters. Dynamic conditions also enhance cell polarization, as evidenced by preferential basal and apical expressions of Na + /K + -ATPase, P-gp, OCT2, and MATE1 , as well as the cellular secretory profile. We demonstrated unidirectional transcellular transport of metformin with a higher efflux than influx ratio, inhibited with OCT2 inhibitor, thus confirming the relevance of our proximal tubule-on-a-chip set up for cation transport investigations. Our proximal tubule-on-a-chip can also be used to explore the interactions between transporters, xenobiotics, and endogenous metabolites, possibly involved in the variability of individual drug responses. This study provides additional evidence that OoC can help bridge the gaps between systemic and local pharmacokinetics., Competing Interests: Declarations. Competing interests: P.M. reports a relationship with Sandoz France that includes: consulting or advisory and funding grants. P.M. reports a relationship with Chiesi SA France that includes: consulting or advisory and funding grants. Other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2025. The Author(s).)