Cachexia is one of oncology’s most feared complications. More than half of patients with advanced non-small cell lung cancer, which accounts for over 85 percent of lung cancer cases, develop the syndrome, which is characterized by anorexia, progressive weight loss and the relentless erosion of skeletal muscle and fat. Unlike simple malnutrition, cachexia cannot be reversed with nutritional support alone. It is driven by systemic inflammation and profound metabolic dysregulation, and it directly contributes to as much as 20 percent of all cancer-related deaths. Patients with cachexia tolerate anti-tumour therapies poorly, suffer diminished quality of life and die sooner. Despite decades of research, no effective pharmacological therapy exists, leaving clinicians to rely on multimodal strategies aimed at reducing inflammation, preserving lean body mass and improving appetite.

The research team, led by Yingjia Zhou, Shaoli Zhao and Huantian Cui, chose Huangqi Guizhi Wuwu Decoction, commonly abbreviated HGWD, because of its well-documented immunomodulatory, anti-inflammatory and microcirculatory properties. The formula is already used clinically in China to manage metabolic dysfunction and immune dysregulation, particularly chemotherapy-related side effects such as peripheral neuropathy. Yet its potential role in tumour-induced cachexia had never been examined. To test it, the researchers implanted Lewis lung carcinoma cells into eight-week-old male C57BL/6 mice, a widely used model of lung cancer cachexia, and randomly assigned fifty animals to five groups: tumour-free controls, untreated cachectic mice, mice treated with the chemotherapy drug cisplatin, and cachectic mice given either a low or high dose of HGWD by daily gastric gavage for fourteen consecutive days.

The results were unambiguous. By days seven and fourteen of treatment, untreated cachectic mice showed a marked decline in grip strength and wire-hang endurance, while mice receiving the high dose of HGWD maintained significantly greater muscle strength. Cisplatin, notably, failed to improve muscle function and in some measures made matters worse. HGWD also increased tumour-free body weight, gastrocnemius and quadriceps muscle mass, and epididymal fat mass, all of which were severely depleted in the untreated cachectic animals. Histological examination confirmed the protective effect: the cross-sectional area of skeletal muscle fibres, which shrank dramatically in cachectic mice, was substantially preserved in the HGWD-treated groups.

At the molecular level, the remedy appeared to reinvigorate the muscle’s own building machinery. Cachectic mice showed sharp reductions in MYHC, MYOD1 and MYOG, proteins essential for myogenesis, along with elevated ATROGIN-1, a key marker of muscle atrophy. HGWD partially restored the myogenic proteins and suppressed ATROGIN-1. The treatment also corrected metabolic and oxidative stress abnormalities in the muscle: glycogen levels, which had collapsed, recovered; lactic acid accumulation diminished; the antioxidant enzymes superoxide dismutase and glutathione peroxidase rebounded; and malondialdehyde, a marker of lipid peroxidation, fell. Intriguingly, HGWD also reduced tumour volume and weight, whereas cisplatin did not rescue, and sometimes worsened, the wasting parameters despite its antitumour action. HGWD-treated mice additionally ate and drank more, a factor the authors acknowledge could contribute to the improvements.

To uncover the mechanism, the team turned to transcriptome sequencing of the gastrocnemius muscle. Comparing untreated cachectic mice with healthy controls revealed widespread disruption of pathways including amino acid biosynthesis, cysteine and methionine metabolism, arginine and proline metabolism, glycolysis, the HIF-1 signalling pathway and cytokine receptor interactions. When the high-dose HGWD group was compared with the untreated cachectic group, the picture shifted dramatically: the most enriched pathways were again dominated by amino acid metabolism, alongside the PPAR signalling pathway, cholesterol metabolism, galactose metabolism and calcium signalling. Crucially, HGWD markedly upregulated genes encoding motor proteins, including Myhas, Mylpf and Myl1, which are critical for maintaining muscle mass, driving myogenesis and regulating contractility.

Untargeted metabolomics of the same muscle tissue told a complementary story. Principal component and discriminant analyses showed that HGWD substantially reshaped the aberrant metabolite profile of cachectic muscle, and pathway enrichment again pointed squarely at amino acid biosynthesis. Among the metabolites restored by the treatment were S-adenosylmethionine, known as SAM, L-arginine, L-tryptophan, L-ornithine, L-leucine and spermidine. Each of these molecules has established links to muscle health: arginine and leucine supplementation has been shown to partially mitigate cachexia in prior studies, accelerated tryptophan catabolism contributes to sarcopenia, ornithine supports mitochondrial and redox function in wasting states, and spermidine plays a well-documented role in protecting against muscle ageing and preserving muscle homeostasis.

The deepest insight came from integrating the two datasets. The researchers found that HGWD upregulated the genes Amd1, Amd2 and Smox while downregulating Gnmt. AMD1 and AMD2 are rate-limiting enzymes that convert SAM into decarboxylated SAM, supplying the propylamine groups needed to synthesize polyamines such as spermidine. SMOX then converts decarboxylated SAM into spermidine, and its expression positively correlates with muscle mass and function. GNMT, by contrast, channels SAM toward S-adenosylhomocysteine, and its dysregulation lowers the SAM/SAH ratio, a change closely linked to muscle ageing and cachexia progression. Western blot analysis confirmed the pattern at the protein level: AMD1 and SMOX rose, GNMT fell. The authors propose that HGWD alleviates cachexia by suppressing GNMT, raising the SAM/SAH ratio and enhancing the conversion of SAM into spermidine, thereby restoring amino acid metabolic homeostasis in skeletal muscle.

The study is not without caveats, which the authors address candidly. Because HGWD also reduced tumour burden and increased food intake, the muscle-protective effect could be secondary to reduced tumour-derived catabolic signalling or improved nutrition rather than a direct metabolic action within muscle tissue; a pair-feeding experiment would be needed to disentangle these possibilities. The findings are also correlational, lacking direct causal proof, and the specific bioactive compounds within the multi-herb formula responsible for the effect remain unidentified. The team plans follow-up work using in vitro myotube atrophy models treated with HGWD-containing serum, combined with siRNA knockdown of AMD1 or SMOX and enzyme inhibitors, alongside multi-omics integration and target-validation techniques such as surface plasmon resonance and drug affinity responsive target stability assays.

Even so, the implications are considerable. With no approved pharmacological therapy for cancer cachexia and more than half of advanced lung cancer patients affected, a well-tolerated, orally available formula that simultaneously preserves muscle, corrects metabolic derangement and modestly inhibits tumour growth represents an unusually attractive therapeutic profile. The identification of the SAM-to-spermidine axis as a plausible mechanism also gives researchers a concrete molecular handle for drug development, whether inspired by the herbal formula itself or by synthetic compounds that mimic its enzymatic effects. For now, the work stands as a rigorous, multi-omics demonstration that a medicine brewed from herbs first described centuries ago can act on modern molecular targets, and it opens a promising path toward clinical evaluation of HGWD in patients whose cancers are stealing their muscle, strength and time.

Subject of Research: Mechanisms of a traditional Chinese medicine formula in treating lung cancer–induced cachexia through amino acid metabolism regulation

Article Title: Huangqi Guizhi Wuwu Decoction Ameliorates Cachexia in Lung Cancer Mice Through Regulating Amino Acid Metabolism: Insights From Transcriptomics, Metabolomics and Experimental Validation

Article References: Zhou, Y., Zhao, S., Shen, H., Wu, J., Li, M., Liu, S., Yang, J., Jin, X., Li, F., & Cui, H. (2026). Huangqi Guizhi Wuwu Decoction Ameliorates Cachexia in Lung Cancer Mice Through Regulating Amino Acid Metabolism: Insights From Transcriptomics, Metabolomics and Experimental Validation. Journal of Cellular and Molecular Medicine, 30(19), Article e71387. https://doi.org/10.1111/jcmm.71387

Image Credits: AI Generated

DOI: 10.1111/jcmm.71387

Keywords: cancer cachexia, lung cancer, Huangqi Guizhi Wuwu Decoction, traditional Chinese medicine, amino acid metabolism, spermidine, S-adenosylmethionine, skeletal muscle atrophy, transcriptomics, metabolomics, Lewis lung carcinoma, myogenesis

The investigation began with an integrated bioinformatics screen of colorectal cancer datasets, from which SUCLG2 emerged as a candidate gene whose expression tracks with disease severity. Multi-omics validation in clinical specimens confirmed the pattern: SUCLG2 levels were significantly downregulated in colorectal cancer tissue compared with healthy tissue, and the degree of loss correlated tightly with advanced TNM staging and poor patient prognosis. Patients whose tumors expressed the least SUCLG2 fared worst, positioning the enzyme not only as a mechanistic player but also as a potential prognostic biomarker that could help clinicians stratify risk at the time of diagnosis.

To probe function, the team manipulated SUCLG2 in colorectal cancer cell lines and in animal models. Functional assays showed that SUCLG2 restrains the proliferation of colorectal cancer cells in culture and suppresses xenograft tumor growth in vivo. When the enzyme was depleted, cells grew more aggressively; when it was restored, growth slowed appreciably. These results established SUCLG2 as a bona fide tumor suppressor rather than a metabolic bystander, raising the central question of how a tricarboxylic acid cycle enzyme exerts such direct control over cancer cell behavior.

The answer, uncovered through transcriptomic, metabolomic, and epigenetic analyses, lies in an unexpected biochemical pathway involving S-adenosylmethionine, or SAM, the universal methyl donor of the cell. SUCLG2 activity reduces intracellular SAM levels. Because SAM is the substrate required by DNA methyltransferases, or DNMTs, to attach methyl groups to DNA, lower SAM availability dampens DNMT activity genome-wide. The consequence for colorectal cancer cells is profound: hypermethylation of tumor suppressor gene promoters is alleviated, and genes silenced by this epigenetic brake can be switched back on.

Among the genes reactivated by this mechanism, one stood out. GADD45G, a growth arrest and DNA damage-inducible gene with well-documented anti-proliferative functions, regained transcriptional activity when SUCLG2 was present. The researchers showed that SUCLG2 demethylates the GADD45G promoter through this SAM-dependent epigenetic remodeling, relieving promoter hypermethylation and restoring GADD45G expression. Gene set enrichment analysis reinforced the picture, revealing that SUCLG2 overexpression activates p53 and apoptosis signaling while inhibiting cell cycle pathways, consistent with GADD45G acting as a conduit between the mitochondrial enzyme and the cell’s central tumor-suppressive machinery.

Causality was tested directly. When the researchers knocked down GADD45G in cells engineered to overexpress SUCLG2, the tumor-suppressive effects of the enzyme were largely abolished. This loss-of-function experiment established GADD45G as a critical downstream mediator of the SUCLG2/p53 signaling axis. In other words, SUCLG2 does not simply slow cancer cells through metabolic exhaustion; it reactivates a specific genetic program, via demethylation of GADD45G, that engages p53-mediated growth inhibition and programmed cell death.

Clinical validation strengthened the mechanistic model considerably. Across patient cohorts, the team confirmed a robust positive correlation between SUCLG2 and GADD45G expression, and, in keeping with the proposed epigenetic mechanism, a negative correlation between SUCLG2 levels and methylation of the GADD45G promoter. Tumors with abundant SUCLG2 tended to carry unmethylated, transcriptionally active GADD45G, whereas SUCLG2-poor tumors showed the silenced, hypermethylated state. These correlative findings in human tissue mirror the experimental results and suggest that the SAM-DNMT-GADD45G axis operates in actual disease, not merely in laboratory models.

The study carries notable therapeutic implications. Epigenetic silencing of tumor suppressor genes is a hallmark of colorectal cancer, and demethylating agents exist but act globally, with limited specificity and considerable toxicity. If SUCLG2 activity, or downstream nodes of its pathway, could be pharmacologically enhanced, it might offer a more targeted way to lift methylation repression specifically at tumor suppressor promoters. Alternatively, the SUCLG2-GADD45G-p53 axis could be exploited indirectly, for example by screening for compounds that mimic the enzyme’s effect on SAM metabolism or DNMT activity. The authors position SUCLG2 as both a promising prognostic biomarker and a candidate therapeutic target, though translating these findings into clinical interventions will require further preclinical development and validation in larger patient populations.

Beyond its immediate clinical relevance, the research adds to a growing appreciation that metabolic enzymes can double as epigenetic regulators. Because metabolites such as SAM, alpha-ketoglutarate, acetyl-CoA, and NAD+ serve as substrates and cofactors for chromatin-modifying enzymes, shifts in cellular metabolism can directly reshape the epigenetic landscape. The SUCLG2 story is a vivid example: a change in the activity of a TCA cycle enzyme propagates through the methyl donor economy of the cell to determine whether a key anti-cancer gene is audible or silenced. As colorectal cancer remains a major clinical challenge, uncovering such regulatory mechanisms may open entirely new avenues for early detection, risk stratification, and treatment.

Subject of Research: SUCLG2-mediated epigenetic activation of the GADD45G-p53 axis in colorectal cancer progression

Article Title: SUCLG2 demethylates GADD45G to activate the p53 pathway and inhibit malignant progression in colorectal cancer

Article References: Guo, T., Lai, S., Yang, K., Tong, J., Liao, G., Lu, L., Jiang, C., Liu, H., Wu, Z., Yang, M., & Guo, J. (2026). SUCLG2 demethylates GADD45G to activate the p53 pathway and inhibit malignant progression in colorectal cancer. Cancer Cell International. https://doi.org/10.1186/s12935-026-04454-5

Image Credits: AI Generated

DOI: 10.1186/s12935-026-04454-5

Keywords: colorectal cancer, SUCLG2, GADD45G, p53 pathway, DNA methylation, demethylation, S-adenosylmethionine, DNA methyltransferase, tumor suppressor, cancer metabolism, epigenetics, prognostic biomarker