Spatial transcriptome mapping identifies <i>Ppara-Anxa2</i> cross-talk in microplastic-induced hepatotoxicity

Microplastics (MPs) are increasingly recognized as an urgent global health concern, with mounting evidence linking their bioaccumulation to chronic disease risks. The liver, as a central organ for metabolic homeostasis and detoxification, is particularly sensitive to sustained MP exposure. However, the mechanisms underlying hepatic responses to polyethylene (PE), the most prevalent yet relatively understudied plastic type, remain poorly defined. By performing combined bulk and spatial transcriptomic analyses, we observed that PE resulted in hepatic dysfunction in mice fed on standard or metabolic dysfunction-associated steatohepatitis (MASH)-inducing diets, driving both globally and spatially distinct transcriptional alterations, including a nuclear receptor (NR), <i>Ppara</i>. Spatial transcriptomics uncovered the cell type heterogeneity and gene expression patterns masked in bulk analyses. Spatial clustering uncovered inflammatory hotspots characterized by reduced cellular diversity and distinct PE-responsive gene signatures. Among these, NR signaling emerged as a key regulatory axis, with Ppara identified as a modulator. We further demonstrated that Ppara regulates <i>Anxa2</i>, a gene involved in damage response and tissue recovery, through enhancer and promoter binding. These findings offer insights into how PE disrupts hepatic homeostasis and underscores the value of spatial transcriptomics in elucidating environmental impacts on tissue organization and gene expression regulation. This study provides a molecular framework for understanding MP-associated disruption of liver pathophysiology and highlights potential targets for therapeutic intervention.