Primate-Specific LINC03040 Drives Myeloid-Dependent Fibrosis in Human MASH Through a STAT3–S100A8 Regulatory 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 fundamental limitation in anti-fibrotic drug development is the profound translational gap between murine models and human immunopathology, particularly with respect to species-specific non-coding regulatory elements. Methods To overcome this translational limitation, 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, coupled with in silico structural interaction modeling. 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. Mechanistically, integrative network inference and structural modeling suggest that LINC03040 functions as a regulatory scaffold linking STAT3 and S100A8 , while excluding PPARG , thereby coordinating pro-fibrotic myeloid signaling. Comparative genomics confirmed that the LINC03040 locus is primate-specific and entirely absent in rodents, underscoring a unique human pathology that is clinically validated by significant co-expression in patient tumors. Conclusion Our findings identify LINC03040 as a primate-specific upstream regulator associated with myeloid-mediated fibrosis in advanced MASH. The evolutionary absence of this locus in rodents underscores the limitations of standard preclinical models, advocating for the use of human-relevant systems to interrogate this immuno-metabolic pathway. Consequently, we propose the LINC03040–STAT3–S100A8 axis as a precise, human-centric targetable regulatory axis with potential relevance for fibrosis intervention.