Primate-Specific LINC03040 Drives MASH Fibrosis via a Myeloid-Dependent Immuno-Metabolic Axis

Background While the recent approval of resmetirom marks a historic milestone in MASH therapy, the effective reversal of established cirrhosis (F4) remains a major unmet clinical need. A critical bottleneck in developing anti-fibrotic drugs for this advanced stage is the profound translational gap between murine models and human immunopathology, particularly regarding species-specific non-coding regulatory elements. Methods To bridge this gap, we integrated bulk transcriptomics from large patient cohorts (n = 216), single-cell–informed deconvolution, and comparative genomic analyses to characterize LINC03040 , a previously unannotated long non-coding RNA that is robustly upregulated in advanced fibrosis. Results LINC03040 emerged not only as a diagnostic marker but as a regulatory hub predictive of patient mortality. Challenging the prevailing stellate cell–centric paradigm, our analysis revealed that LINC03040 is spatially restricted to infiltrating myeloid populations, specifically monocytes and dendritic cells, rather than resident stromal cells. Mechanistically, LINC03040 drives a distinct immuno-metabolic reprogramming, its upregulation coincides with the induction of steroid biosynthesis and foam-cell–like signatures, which in turn fuel a pro-fibrotic cascade via the S100A8/STAT3 signaling axis. Crucially, comparative genomics confirmed that the LINC03040 locus is primate-specific and entirely absent in rodent genomes. Conclusion Our findings identify LINC03040 as a human-specific driver of myeloid-mediated fibrosis in advanced MASH. The evolutionary absence of this locus in mice underscores the limitations of standard preclinical models and advocates for the prioritization of human-relevant experimental systems to target this novel immuno-metabolic axis.