Abstract Body (Do not enter title and authors here): Hypothyroidism (HypoTH) is an independent and major risk factor for myocardial infarction (MI). However, long noncoding RNA (lncRNA; ncRNAs>200 bp) mechanisms in the cardiac thyroid hormone (TH) pathway are unclear. An array of in vitro, in vivo, computational, and statistical methods was employed. Paigen high-fat (PHF)-fed homozygous HypoE mice died rapidly (median survival [ms] 26 days) with severe MI, cardiac fibrosis, hypertrophy, inflammation, lipid deposition, and heart failure. So, we used cholate-free PHF diet, which showed more gradual mortality (ms: 41.5 days) with serum HypoTH, cardiac hypertrophy, splenomegaly, and alterations in real-time differential expression of multiple inflammatory/immune left ventricular (LV) lncRNAs, especially the lncRNA, XRik (>2-fold; p<0.05). Oral T3 therapy restored LV contractility, atrial refractory period, expression levels of LV epigenetic enzymes and lncRNAs, especially XRik, without increases in heart rate or hypertrophy. We genetically manipulated XRik using siRNAs, overexpression, and CRISPRa (dCas9)-based activation strategies in HL1 adult mouse myocytes, primary adult mouse ventricular myocytes, and/or primary adult mouse ventricular nonmyocytes (fibroblasts). XRik overexpression improved cell viability against Doxorubicin or H2O2 injury (p<0.05). While XRik siRNA inhibited cardiac cell viability following low-iodine diet-induced HypoTH in control mice, both overexpression and CRISPRa-activation improved cell viability. siRNA-induced increase in proapoptotic Cytochrome C levels was attenuated by T3 (and CRISPRa; p<0.05). Our LV lncRNA-seq-based prediction of XRik’s interaction with an miRNA was mediated by T3 via dual-luciferase assays. In vivo lentiviral CRISPRa XRik delivery improved LV fractional shortening in cholate-free PHF homozygous HypoE mice without significant adverse effects on hypertrophy or heart rate (p<0.05). LV mRNA-sequencing identified alterations in several genes/transcripts in these mice, which were improved following in vivo XRik CRISPRa. Enrichment analyses showed improvements in genes/transcripts related to pathways including TH synthesis, cardiac contraction, lipid metabolism, ATP/Ca++ binding, inflammation, apoptosis, etc. CRISPRa in vivo also significantly reduced the levels of multiple proinflammatory cytokines (p<0.05). In conclusion, we uncovered a novel mechanism by which T3 regulates XRik in mediating cardioprotection in high-fat-diet-induced atherosclerosis-driven MI.