Leiomodin 1 deficiency promotes lipid accumulation and redirects gene regulatory programs in smooth muscle cells exposed to oxidized LDL.

The transition of smooth muscle cells (SMCs) from a contractile to a synthetic, lipid-accumulating phenotype is a central driver of atherosclerosis. We previously identified leiomodin 1 ( LMOD1 ), an SMC-enriched gene, as a critical regulator of SMC phenotypic modulation and atherosclerosis in mice. However, whether LMOD1 exerts similar effects in human SMCs, and the mechanisms underlying its anti-atherogenic effects, remain unclear. Here, we show that LMOD1 -deficient human SMCs exposed to oxidized low-density lipoprotein (oxLDL) exhibit increased intracellular lipid accumulation, consistent with a foam cell-like phenotype. Bulk RNA-sequencing using a Condition × Treatment interaction-term design identified LMOD1 -dependent oxLDL-responsive transcriptional changes, marked by altered atherogenic gene expression, including dysregulated LDLR and BMP2 responses. Integrative regulatory network inference revealed that LMOD1 deficiency disrupted the coordinated oxLDL-induced gene-targeting program observed in control SMCs. Response-vector geometry further demonstrated that LMOD1 loss redirected the regulatory response to oxLDL along a near-orthogonal axis in gene-targeting space. Interaction-term targeting and condition-specific propagation analyses uncovered widespread target-gene rewiring and altered transcription factor influence, including FOXO1 - and RUNX2 -associated inferred regulatory routes. Together, these findings provide a potential mechanistic basis for the anti-atherogenic effects of LMOD1 in human SMCs.