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In this study, we showed that after continuous oral consumption of high-fat (HF) diets containing M<jats:sub>4<\/jats:sub>N, the M<jats:sub>4<\/jats:sub>N concentration in most of the organs in mice reached ~1 \u03bcM (the M<jats:sub>4<\/jats:sub>N concentration in intestines and fat pads was as high as 20\u201340 \u03bcM) and treatment with the combination of M<jats:sub>4<\/jats:sub>N with temozolomide (TMZ) suppressed glycolysis and the tricarboxylic acid cycle in LN229 human glioblastoma implanted in xenograft mice. Combination treatment of M<jats:sub>4<\/jats:sub>N with TMZ also reduced the levels of lactate dehydrogenase A (LDHA), a key enzyme for glycolysis; lactate, a product of LDHA-mediated enzymatic activity; nicotinamide phosphoribosyltransferase, a rate-limiting enzyme for nicotinamide adenine dinucleotide plus hydrogen (NADH)\/NAD+ salvage pathway; and NAD+, a redox electron carrier essential for energy metabolism. It was also shown that M<jats:sub>4<\/jats:sub>N suppressed oxygen consumption in cultured LN229 cells, indicating that M<jats:sub>4<\/jats:sub>N inhibited oxidative phosphorylation. Treatment with M<jats:sub>4<\/jats:sub>N and TMZ also decreased the level of hypoxia-inducible factor 1A, a major regulator of LDHA, under hypoxic conditions. The ability of M<jats:sub>4<\/jats:sub>N to suppress energy metabolism resulted in induction of the stress-related proteins activating transcription factor 4 and cation transport regulator-like protein 1, and an increase in reactive oxygen species production. In addition, the combination treatment of M<jats:sub>4<\/jats:sub>N with TMZ reduced the levels of oncometabolites such as 2-hydroxyglutarate as well as the aforementioned lactate. M<jats:sub>4<\/jats:sub>N also induced methylidenesuccinic acid (itaconate), a macrophage-specific metabolite with anti-inflammatory activity, in tumor microenvironments. Meanwhile, the ability of M<jats:sub>4<\/jats:sub>N to suppress energy metabolism prevented obesity in mice consuming HF diets, indicating that M<jats:sub>4<\/jats:sub>N has beneficial effects on normal tissues. The dual ability of combination treatment with M<jats:sub>4<\/jats:sub>N to suppress both energy metabolism and oncometabolites shows that it is potentially an effective therapy for cancer.<\/jats:p>","DOI":"10.1371\/journal.pone.0285536","type":"journal-article","created":{"date-parts":[[2023,5,25]],"date-time":"2023-05-25T17:34:29Z","timestamp":1685036069000},"page":"e0285536","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":8,"title":["Tetra-O-methyl-nordihydroguaiaretic acid inhibits energy metabolism and synergistically induces anticancer effects with temozolomide on LN229 glioblastoma tumors implanted in mice while preventing obesity in normal mice that consume high-fat diets"],"prefix":"10.1371","volume":"18","author":[{"given":"Kotohiko","family":"Kimura","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jong Ho","family":"Chun","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu-Ling","family":"Lin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu-Chuan","family":"Liang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0800-1484","authenticated-orcid":true,"given":"Tiffany L. 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