Background: The liver X receptors are oxysterol-activated nuclear hormone receptors that regulate cholesterol homeostasis and de novo lipogenesis. TLC-2716 is an oral, liver-targeted inverse agonist of LXRα/β in development for severe hypertriglyceridemia (SHTG) and NASH. Methods: In this randomized, double-blind, placebo (PBO)-controlled Phase 1 study (NCT05483998), healthy subjects (n=8/2 TLC-2716 vs PBO/cohort) received single ascending doses (SAD) of TLC-2716 (0.5, 2, 6, 12, or 20 mg) or multiple ascending doses (MAD) QD for 14 days (0.5, 2, 6, or 12 mg) while fed or 6 mg fasted. Safety, PK, serum lipid parameters by NMR LipoProfile ® , and gene expression in PBMCs were evaluated. Results: The proportion of subjects with adverse events (AEs) was 60% with PBO and 13-50% with TLC-2716 in the SAD cohorts (n=50), and 40% and 13-88%, respectively, in the MAD cohorts (n=50). All AEs were mild except an unrelated, Grade 2 thrombophlebitis in a subject on TLC-2716 2 mg. TLC-2716 was rapidly absorbed (T max 2-4h) with a short steady-state half-life (T 1/2 ~1.5-2.5h) and low maximal plasma concentrations (C max <7 ng/mL), consistent with rapid hepatic uptake. With fed dosing, TLC-2716 AUC and C max increased less than dose proportionally and were 25-50% lower on Day 14 vs Day 1. With fasted dosing, exposures were similar on Days 1 and 14 and ~3-fold higher than with fed dosing. Significant, dose-dependent reductions in serum triglycerides, total and LDL-C, total and small LDL particles, and TG/HDL-C ratio—but not HDL-C—were observed with TLC-2716 ( Figure ). Lipid reductions were greatest in subjects with higher baseline values. TLC-2716 did not impact LXR target gene expression (e.g., reverse cholesterol transporters ABCA1 , ABCG1 ) in PBMCs, supporting its liver-targeted profile. Conclusion: The liver-targeted LXR inverse agonist TLC-2716 was well tolerated and caused significant lipid lowering in healthy subjects, supporting its evaluation in patients with SHTG and NASH.