Dipeptidyl peptidase 9 (DPP9) is a direct inhibitor of NLRP1, but how it affects inflammasome regulation in vivo is not yet established. Here, we report three families with immune-associated defects, poor growth, pancytopenia, and skin pigmentation abnormalities that segregate with biallelic DPP9 rare variants. Using patient-derived primary cells and biochemical assays, these variants were shown to behave as hypomorphic or knockout alleles that failed to repress NLRP1. The removal of a single copy of Nlrp1a/b/c , Asc , Gsdmd , or Il-1r , but not Il-18 , was sufficient to rescue the lethality of Dpp9 mutant neonates in mice. Similarly, dpp9 deficiency was partially rescued by the inactivation of asc , an obligate downstream adapter of the NLRP1 inflammasome, in zebrafish. These experiments suggest that the deleterious consequences of DPP9 deficiency were mostly driven by the aberrant activation of the canonical NLRP1 inflammasome and IL-1β signaling. Collectively, our results delineate a Mendelian disorder of DPP9 deficiency driven by increased NLRP1 activity as demonstrated in patient cells and in two animal models of the disease.

Exome sequencing has introduced a paradigm shift for the identification of germline variations responsible for Mendelian diseases. However, non‐coding regions, which make up 98% of the genome, cannot be captured. The lack of functional annotation for intronic and intergenic variants makes RNA‐seq a powerful companion diagnostic. Here, we illustrate this point by identifying six patients with a recessive Osteogenesis Imperfecta (OI) and neonatal progeria syndrome. By integrating homozygosity mapping and RNA‐seq, we delineated a deep intronic TAPT1 mutation (c.1237‐52 G>A) that segregated with the disease. Using SI‐NET‐seq, we document that TAPT1 's nascent transcription was not affected in patients' fibroblasts, indicating instead that this variant leads to an alteration of pre‐mRNA processing. Predicted to serve as an alternative splicing branchpoint, this mutation enhances TAPT1 exon 12 skipping, creating a protein‐null allele. Additionally, our study reveals dysregulation of pathways involved in collagen and extracellular matrix biology in disease‐relevant cells. Overall, our work highlights the power of transcriptomic approaches in deciphering the repercussions of non‐coding variants, as well as in illuminating the molecular mechanisms of human diseases.

Dipeptidyl peptidase 9 (DPP9) is a direct inhibitor of NLRP1, but how it impacts inflammasome regulation in vivo is not yet established. Here, we report two families with immune-associated defects, skin pigmentation abnormalities and neurological deficits that segregate with biallelic DPP9 rare variants. Using patient-derived primary cells and biochemical assays, these variants are shown to behave as hypomorphic or loss-of-function alleles that fail to repress NLRP1. Remarkably, the removal in mice, of a single copy of either Nlrp1a/b/c, Asc, Gsdmd, Il-1r , but not Il-18 , was sufficient to rescue the lethality of Dpp9 mutant neonates. These experiments suggest that the deleterious consequences of DPP9 deficiency are mostly driven by the aberrant activation of the canonical NLRP1 inflammasome and IL-1β signaling. Collectively, our results delineate a Mendelian disorder of DPP9 deficiency driven by increased NLRP1 activity as demonstrated in patient cells and in a mouse model of the disease.

The liver is a central regulator of systemic metabolism and exhibits exceptional regenerative capacity, yet aging progressively impairs hepatic resilience through metabolic dysregulation, mitochondrial dysfunction, epigenetic instability, and chronic inflammation. Marine ecosystems constitute a vast and underexplored source of structurally diverse bioactive compounds that have evolved to modulate conserved stress response and homeostatic pathways. This review synthesizes current preclinical evidence demonstrating how marine-derived metabolites target key molecular axes implicated in liver aging, including energy sensing, redox balance, mitochondrial quality control, inflammatory signaling, and chromatin-associated regulation. Rather than focusing solely on isolated hepatoprotective effects, we frame marine bioactives within an aging biology perspective, highlighting their ability to modulate pathways associated with cellular plasticity and resilience. We further propose that this mechanistic convergence provides a theoretical framework for exploring marine compounds as potential adjunctive modulators within emerging, experimental liver rejuvenation strategies, including partial cellular reprogramming approaches that require coordinated metabolic and epigenetic control. While acknowledging that direct reversal of liver aging remains to be clinically established, integrating marine chemodiversity with contemporary aging and regenerative biology outlines a conceptual roadmap for developing liver-directed interventions targeting aging-related vulnerability as a fundamental driver of disease.

The protective machinery of the skin opposes external agents by barrier and innate and adaptive immunity. The local interplay in the epithelial-i | POSTER