Baricitinib Augments Lonafarnib Therapy to Preserve Colonic Homeostasis and Microbial Balance in a Mouse Model of Progeria.

Hutchinson-Gilford Progeria Syndrome (HGPS) is a fatal genetic disorder caused by progerin, a mutant lamin A variant that disrupts nuclear architecture and drives systemic cellular dysfunction. Gastrointestinal (GI) involvement in HGPS remains poorly understood, despite growing evidence of gut abnormalities and microbial dysbiosis in progeroid mouse models. Here, we provide the first comprehensive characterization of colonic pathology in LmnaG609G/G609G mice and assess the therapeutic impact of baricitinib (Bar), a JAK-STAT inhibitor, lonafarnib (FTI), the only FDA-approved therapy, and their combination on colonic health. Bar + FTI combination therapy most effectively lowered progerin levels, preserved colonic architecture and epithelial regeneration markers, while also reducing inflammation, cellular senescence, and early fibrotic changes. Notably, FTI monotherapy aggravated inflammation via STAT1 activation, an effect reversed by Bar co-administration. Bar also emerged as the primary driver in mitigating colonic tissue senescence, highlighting its role in supporting intestinal homeostasis. In addition, we observed marked microbial dysbiosis in HGPS mice, particularly in late-stage disease. While both monotherapies induced distinct shifts in gut microbiota, combination therapy preserved a profile more closely resembling healthy controls. These findings expand the current understanding of GI involvement in HGPS and identify the colon as a site where JAK-STAT inhibition enhances the therapeutic profile of FTI.