Claire Gao

Supplementary Figure S5. Gene set enrichment analysis in MM cells following ND-646 treatment, and evaluation of cell growth under combined treatment with ND-646 and simvastatin.

Supplementary Figure S4. Impact of pharmacological inhibition (ND-630 and ND-646) and ACC1 knockdown on MM cell viability, proliferation, and de novo lipogenesis (DNL) rates in MYC overexpressed MM cells.

Supplementary Figure S1. Expression profiling and correlation analysis of MYC and ACC1 in patients with newly diagnosed multiple myeloma (NDMM).

Supplementary Figure S2. Quantitative analysis of ACACA expression in multiple myeloma (MM) cell lines.

Supplementary Figure S3. Representative western blot analysis showing protein levels of ACC1, phosphorylated ACC (pACC), and MYC in MM cells.

Purpose: In multiple myeloma, tumor cells reprogram metabolic pathways to sustain growth and monoclonal immunoglobulin production. This study examines acetyl-CoA carboxylase 1 (ACC1), the enzyme driving the rate-limiting step in de novo lipogenesis, in multiple myeloma metabolic reprogramming, particularly in c-MYC (MYC)–driven subtypes. Experimental Design: ACC1 expression was evaluated across multiple myeloma genetic subgroups, focusing on MYC translocations. Functional studies using ACC1 inhibitors and genetic knockdown assessed multiple myeloma cell growth, lipid synthesis, and metabolic homeostasis in vitro and in vivo. The role of MYC overexpression in ACC1 sensitivity was examined, with palmitate rescue experiments. Lipidomic analysis and assessments of endoplasmic reticulum (ER) stress, protein translation, and oxidative damage elucidated underlying mechanisms. Results: ACC1 was overexpressed in MYC-translocated multiple myeloma. Its inhibition or knockdown reduced multiple myeloma cell growth in vitro and in vivo, particularly in MYC-overexpressing cells. ACC1 knockdown suppressed de novo lipid synthesis, partially rescued by palmitate. Lipidomic disruptions increased cholesterol ester desaturation and altered phospholipid ratios, inducing ER stress, impaired translation, protein carbonylation, oxidative damage, and apoptosis. Conclusions: ACC1 is a metabolic vulnerability in MYC-driven multiple myeloma. Inhibiting ACC1 disrupts lipid homeostasis, induces ER stress, and causes oxidative damage, impairing cell survival. Targeting lipid synthesis pathways, especially in MYC-dependent subtypes, offers a promising therapeutic strategy for multiple myeloma.