La dott.ssa Antonella Muzzo, attualmente assegnista di ricerca presso l’Università degli Studi di Trieste, ha ricevuto l’ASCPT 2026 Presidential Trainee Award, prestigioso riconoscimento conferito dalla American Society for Clinical Pharmacology and Therapeutics (ASCPT) a giovani ricercatori distintisi per l’eccellenza scientifica.

Il premio è stato attribuito per il progetto di dottorato svolto presso il Dipartimento di Scienze Mediche dell’Università di Trieste e l’IRCCS Burlo Garofolo, sotto la supervisione della prof.ssa Marianna Lucafò, del Dipartimento di Scienze della Vita, e del prof Gabriele Stocco, del Dipartimento di Scienze Mediche, in collaborazione con la prof.ssa G. Meroni e la dott.ssa E. Lazzari, del Dipartimento di Scienze della Vita, presentato sotto forma di poster dal titolo:

“THIOPURINE TREATMENT RESPONSES IN PEDIATRIC INFLAMMATORY BOWEL DISEASE ARE DETERMINED BY A NEWLY IDENTIFIED TRIM32-CGAS-STING PATHWAY: A PHARMACOKINETIC STUDY IN ORGANOIDS”.

La dott.ssa Muzzo presenterà il lavoro in occasione del congresso annuale della Società, che si terrà a Denver (USA) dal 4 al 6 marzo 2026.

Abstract:

Background: Azathioprine (AZA) and mercaptopurine (MP) are thiopurines used in inflammatory bowel disease. This study investigated their possible direct effect in gut epithelium because it is still poorly understood.

Methods: Cytotoxicity was evaluated by Cell Titer or MTT assays on pediatric patient-derived colonic organoids (n=44) and the intestinal LS180 cells. Drug metabolites were measured by LC-MS/MS. Proteomic REACTOME enrichment analyses were performed on 5 organoids exposed 72 hours (h) to 0.2μM AZA or MP. TRIM32 was silenced in LS180 cells (siRNA 40nM 72h). LS180 cells were exposed 72h to 50μg/mL cGAMP alone or with AZA or MP (0.2μM and 2μM). Proteins were detected by immunoblotting. Significant associations were evaluated by Spearman’s test or ANOVA/t-test.

Results: In organoids thiopurines induced dose-dependent cytotoxicity with inter-patient variability, which was related to the expression of metabolic enzymes ITPA, TPMT, NUDT15 (p=0.05 ρ=-0.8; MP 0.011 ρ=-0.8) and the methylated metabolite MeTIMP (AZA p=0.04 ρ=-0.7; MP p =0.04; ρ=-0.7).
Proteomic analysis identified the E3-ubiquitin ligase TRIM32 as a novel thiopurines target, with reduced levels after thiopurine treatment (p=0.008). TRIM32, a modulator of cGAS-STING pathway, negatively correlated with thiopurines sensitivity in organoids (AZA p=0.006 ρ=-0.8; MP p=0.002 ρ=-0.9). TRIM32 silencing in LS180 cells increased MP resistance (p < 0.0001).
Compared to LS180 cells exposed only to cGAMP, the co-treatment with 0.2μM or 2μM MP reduced cGAMP-induced STING activation (p=0.034 and p=0.04) and TRIM32 (p=0.005). cGAMP increased P65 activation under basal condition (p=0.008) and after MP co-treatment at 0.2μM and 2μM compared to MP alone (p=0.04 and p=0.024). MP 0.2μM or 2μM reduced P65 activation (t-test p=0.008, and p=0.0035).

Conclusion: Thiopurines inter-patient response is mainly influenced by metabolic enzymes and MeTIMP levels. Thiopurines exert an anti-inflammatory role in gut epithelium modulating TRIM32-cGAS-STING and NF-κB/P65 pathways