P2, N=50, Recruiting, Wake Forest University Health Sciences | Trial completion date: Apr 2030 --> Mar 2028

Encouragingly, agents such as the fatty acid synthase inhibitor TVB-2640 and the glutaminase inhibitor CB-839 have already entered clinical trials. We recognize that adverse effects on normal tissues and drug resistance driven by metabolic plasticity represent major challenges for metabolism-targeted therapies. Accordingly, we systematically summarize innovative strategies that offer new therapeutic possibilities, including targeting multiple metabolic pathways through combination therapy to enhance efficacy, combining metabolic inhibitors to overcome resistance to conventional anticancer agents, leveraging metabolic reprogramming for early cancer detection, and exploring emerging approaches such as immunometabolism and metabolomics.

P2, N=17, Active, not recruiting, Mayo Clinic | Trial completion date: Dec 2025 --> Jun 2026

P2, N=50, Recruiting, Wake Forest University Health Sciences | Trial completion date: Apr 2028 --> Apr 2030 | Trial primary completion date: Feb 2026 --> Feb 2028

Fatty acid synthase (FASN), the rate limiting enzyme of de novo lipogenesis, is an important regulator of CRC progression, but the FASN inhibitor TVB-2640 showed only modest efficacy in reducing tumor burden in pre-clinical studies, suggesting combination strategies might be required to prolong patient survival. Importantly, combining FASN inhibition with the chemotherapeutic drug irinotecan synergistically decreased xenograft tumor growth and delayed tumor relapse, which was potentiated by the PARP inhibitor olaparib as maintenance treatment. Taken together, this study describes a therapeutic strategy in which FASN inhibitors can be utilized to delay tumor recurrence after chemotherapy, which is a major challenge in patients with CRC.

P1, N=128, Recruiting, Sagimet Biosciences Inc. | Trial completion date: Jan 2026 --> Jun 2026 | Trial primary completion date: Dec 2025 --> May 2026

P1, N=40, Completed, Sagimet Biosciences Inc. | Active, not recruiting --> Completed

Despite these efforts, only a handful of inhibitors have entered clinical trials, such as 3-V Biosciences-2640 (denifanstat) and repurposed omeprazole, and none have received regulatory approval to date. Despite progress with novel and repurposed inhibitors, none have gained approval. This review critically examines past efforts, current challenges, and offers insights to guide future development of effective fatty acid synthase-targeting cancer therapeutics.

P3, N=240, Completed, Ascletis Pharmaceuticals Co., Ltd. | Active, not recruiting --> Completed | Trial completion date: Mar 2026 --> Nov 2025

P1, N=30, Recruiting, Weill Medical College of Cornell University | Trial completion date: Nov 2026 --> Jan 2029 | Trial primary completion date: Nov 2025 --> Jan 2027

Using an AI-driven prediction model and in vitro/in vivo assays, fatty acid synthase inhibitor TVB-2640 is identified as a potential therapeutic agent for disrupting metabolic vulnerability and suppressing NSCLC BMs. These findings provide novel insights into NET-dependent cellular interactions that sustain the pro-metastatic microenvironment underlying NSCLC BMs, offering robust development of novel metabolism-based therapeutic strategies to combat this lethal complication.

Our study reveals a distinct lipid signature in gastric metaplasia characterized by TG and LD accumulation, providing novel therapeutic insights into targeting lipid metabolism to prevent GIM malignant transformation and reduce cancer risk.