bims-stacyt 2026-06-07 papers

Cell Death Dis. 2026 Jun 03.

PEBP4 alleviates muscle wasting in lung cancer cachexia via KEAP1-NRF2-mediated redox homeostasis.

Yaru Xia, Yuqi Han, Weiquan Li, Tiexi Yu, Diaoyi Tan, Daojia Miao, Wen Li, Jiaming Wu, Qianqian Luo, Jiemin Li, Pian Liu, Hongli Liu, Guixiao Huang, Xiaoping Zhang, Hongmei Yang.

Cancer-associated cachexia (CAC) is a multifactorial metabolic syndrome characterized by progressive skeletal muscle wasting. However, the molecular link between tumor metabolic stress and muscle degradation remains elusive. Here, we identify phosphatidylethanolamine-binding protein 4 (PEBP4) as a key regulator of muscle homeostasis under cachectic conditions. PEBP4 expression is markedly suppressed in lung cachectic models and is inversely correlated with tumor-derived lactate levels. Mechanistically, PEBP4 stabilizes NRF2 by competitively binding to KEAP1, enhancing antioxidant defense, inhibiting NF-κB signaling, and downregulating muscle atrophy-related genes MuRF1 and Fbxo32 (also known as Atrogin-1). In vitro and in vivo overexpression of PEBP4 mitigates oxidative stress, preserves muscle mass, and improves strength and endurance in Lewis lung carcinoma tumor-bearing mice. These protective effects are significantly attenuated by NRF2 inhibition, highlighting its critical role in PEBP4-mediated signaling. Collectively, our findings uncover a tumor lactate-PEBP4-NRF2 axis linking cancer metabolism to redox imbalance and muscle wasting, and suggest the therapeutic potential of targeting the PEBP4-NRF2 pathway in lung cancer-associated cachexia.

DOI: https://doi.org/10.1038/s41419-026-08925-5

J Cachexia Sarcopenia Muscle. 2026 Jun;17(3): e70318

Novel Long-Acting Ghrelin Analogue PEP-064 Restores Energy Balance in C26 and Lewis Lung Carcinoma-Induced cachexia in Mice.

BACKGROUND: Cancer cachexia is a debilitating syndrome marked by involuntary weight loss resulting from reduced food intake and intricate metabolic reprogramming. Despite its high prevalence, cancer cachexia remains undertreated, with a lack of effective and approved pharmacotherapies. Ghrelin has emerged as a therapeutic target for cancer cachexia due to its beneficial effects on energy balance. However, the clinical application of ghrelin is hampered by its short half-life. In this study, we introduce PEP-064, a novel stabilized, long-acting and efficacious ghrelin analogue and assess its effects on C26-induced and Lewis lung carcinoma (LLC)-induced cachexia in mice.
METHODS: The in vivo efficacy of PEP-064 was evaluated in healthy CD-1 mice after repeated dosing for 7 days and in the C26 and LLC cancer cachexia mouse models. Additionally, the pharmacokinetic profile and whole brain neuronal activity mapping were conducted in healthy mice following a single subcutaneous injection of PEP-064. Growth hormone secretion was measured in healthy rats following a single administration of PEP-064.
RESULTS: In healthy mice, PEP-064 exhibited a dose-dependent (100, 300 and 1000 nmol/kg) increase in both delta body weight (BW) and total food intake (FI) compared to the vehicle (BW: 2.7 g vs. 3.5, 4.8 and 5.3 g; FI: 50 g vs. 57 g, 60 and 70 g). In the C26 model, PEP-064 protected against loss of tumour-free (TF) BW (-1.2 g vs. 1.7 g, p < 0.0001), increased food intake (33 g vs. 41 g, p < 0.01), prevented losses in fat (-1.1 g vs. 0.9 g, p < 0.0001) and lean mass (-0.07 g vs. 0.4 g, p < 0.05) without affecting tumour growth. In the LLC model, PEP-064 induced hyperphagia (52.2 g vs. 61.6 g, p < 0.0001) and protected against TF-BW loss (-1.4 g vs. - 0.01 g, p < 0.05) and fat mass loss (-0.9 g vs. 0.8 g, p < 0.0001). In mice, PEP-064 had a T1/2 of 6.6 h and a Tmax at 4 h. PEP-064 increased neuronal activity (c-Fos) in the hypothalamic and amygdala regions, with the tuberal nucleus of the hypothalamus showing the highest increase compared to the vehicle (p < 0.05). Lastly, circulating growth hormone was increased 20 min after subcutaneous PEP-064 dosing, peaking at 30 min at 93 ng/mL and returning to approximately baseline by 120 min.
CONCLUSIONS: The novel, long-acting and efficacious ghrelin analogue, PEP-064, restored energy balance in cancer cachexia by increasing food intake and body weight, preserving lean mass and increasing adiposity, without affecting tumour growth. Considering the unmet medical need for safe and effective treatments for cachexia, our study demonstrates the feasibility of a long-acting ghrelin approach for treating cancer cachexia.

Keywords: C26 colon carcinoma; Lewis lung carcinoma; cancer cachexia; ghrelin; peptide

DOI: https://doi.org/10.1002/jcsm.70318

Signal Transduct Target Ther. 2026 Jun 05. pii: 219. [Epub ahead of print]11(1):

The Gdf15-xenobiotic receptor axis shapes NK cell maladaptation predicting cold tumors under environmental stress.

Juil Kim, Ki-Hyung Kim, Zhimin Du, Hoyoung Jeong, Hyung-Joon Yoon, Won Hoon Song, Yuseok Moon.

Cold tumors, including epithelial ovarian cancer (EOC), mostly arise from sporadic factors, particularly hormonal and environmental influences, and are characterized by limited immune cell infiltration. Growth differentiation factor 15 (Gdf15) is increasingly recognized as a prognostic marker for EOC, but its role in harsh tumor environments, including immune surveillance and xenobiotic stress, remains underexplored. Analysis via clinical and cellular analyses revealed that EOC cell-derived Gdf15 facilitates the biological actions of aryl hydrocarbon receptor (AhR) signaling in the tumor immune niche. Notably, AhR signaling is enriched in natural killer (NK) cells following chemotherapy and during relapse, which is correlated with poor patient prognosis. Moreover, elevated Gdf15 levels are associated with reduced postprogression survival, indicating the involvement of the Gdf15-AhR axis in chemoresistance and tumor progression. While Gdf15-high EOC cells exhibit resistance to NK actions, EOC cell-derived Gdf15 enhances NK cell surveillance against Gdf15-low EOC cells, a predominant population in primary tumors. Despite the initial anticancer activity of NK cells, the AhR signaling-high NK cell population eventually displays stress-associated features of cellular exhaustion with diminished immunological surveillance markers during malignancy. This AhR-associated exhaustive stress process in NK cells was further validated in allograft and xenobiotic exposure models, closely mirroring clinical observations. Although Gdf15-modulated AhR signaling initially mediates anticancer effects, the prolonged interplay between Gdf15 and AhR is linked to impaired NK cell surveillance. The prediction of adverse outcomes via the Gdf15-AhR axis provides new insights into the malignant evolution of the tumor-NK cell niche and the environmental susceptibility of EOC progression.

DOI: https://doi.org/10.1038/s41392-026-02690-9

J Immunother Cancer. 2026 Jun 03. pii: e014927. [Epub ahead of print]14(6):

Glucose restriction reprograms lipid metabolism and enhances immunotherapy through ZNRF3-Wnt-SCD signaling axis.

Yarui Ma, Qi Zhang, Zhewen Wei, Zhendiao Zhou, Xue Wang, Chungui Xu, Xiu Liu, Shitong Min, Peng Wang, Fangqing Yuan, Yuchen Jiao, Guangwen Yuan.

BACKGROUND: Glucose restriction is a hallmark of the tumor microenvironment (TME), yet how tumor cells adapt to this metabolic stress and the impact of metabolic reprogramming on the TME remains incompletely understood.
METHODS: A genome-wide CRISPR knockout positive screen was performed to identify key mediators of cellular adaptation to glucose restriction. Using biochemistry, molecular biology, metabolomics and confocal immunofluorescent microscopy to elucidate the underlying molecular mechanisms. Additionally, single-cell RNA sequencing and orthotopic tumor models were used to characterize TME remodeling and assess therapeutic efficacy.
RESULTS: We identified zinc and ring finger 3 (ZNRF3) as a key mediator of cellular adaptation to glucose restriction through genome-wide CRISPR/Cas9 screening. Multiple tumor cells adaptively survived in glucose-restricted conditions with downregulated ZNRF3. Mechanistically, low glucose suppresses ZNRF3 expression, leading to Wnt pathway activation and subsequent transcriptional repression of stearoyl-CoA desaturase (SCD). This metabolic rewiring enhances antitumor immunity by increasing T-cell infiltration and cytotoxicity. In multiple preclinical models, dietary glucose restriction synergizes with immune checkpoint blockade to suppress tumor growth.
CONCLUSION: These findings establish the ZNRF3-Wnt-SCD axis as a metabolic checkpoint controlling tumor cell fate under glucose restriction and provide a rationale for combining dietary intervention with immunotherapy.

Keywords: Immune Checkpoint Inhibitor; Immunotherapy; Nutrition; Tumor Burden

DOI: https://doi.org/10.1136/jitc-2026-014927

BMC Res Notes. 2026 Jun 02.

Bilateral versus unilateral injection of Lewis lung carcinoma cells in female mice fed a Western diet: effects on cachexia severity, tumor burden, and tumor ulcerations.

Rebecca F Rodriguez, Lauren F Boone, Michelle L Law.

OBJECTIVE: Cachexia leads to weight loss and muscle wasting, reducing quality and length of life for advanced cancer patients. There is increasing interest in studying cachexia in the context of obesity due to its increasing worldwide prevalence. C57Bl6 mice are susceptible to diet-induced obesity and Lewis lung carcinoma (LLC)-induced cachexia; however, challenges with this model include large tumor sizes with ulcerations and a mild cachexia phenotype in females. Therefore, this study tested the effect of injecting fewer LLC cells compared to previous studies at either one or two sites in female mice on a Western diet. We hypothesized this would decrease tumor growth rate and ulcerations, enabling longer study duration and overt cachexia development.
RESULTS: Contrary to our hypothesis, over half of tumors developed ulcerations, requiring study termination at 19 days. However, mice with one and two tumors still developed mild and severe cachexia, respectively. Total tumor mass was less predictive of cachexia severity than tumor number. These data show bilateral injections of 250,000 LLC cells induced significant cachexia in female mice on a Western diet, despite a shortened study timeline. These findings are important for improving pre-clinical modeling of cachexia in the context of Western-style obesogenic diets and obesity.

Keywords: Atrophy; Cancer; High-fat diet; Mouse model; Muscle; Obesity; Weight loss

DOI: https://doi.org/10.1186/s13104-026-07902-7

Nat Commun. 2026 Jun 03.

The mannosyltransferase DPM1 regulates the activity of ER-stress sensor IRE1 in colorectal cancer.

Most colorectal cancer (CRC) patients exhibit resistance to immune checkpoint blockade (ICB), limiting treatment efficacy. Activating the unfolded protein response sensor IRE1α in cancer cells can induce anticancer immune responses, yet its regulation remains unclear. Here we identify Dolichyl-Phosphate Mannosyltransferase 1 (DPM1) as a regulator of IRE1 expression and activity using BioID screen. Analysis of CRC patient RNA-sequencing data reveals that low DPM1 expression correlates with an IRE1-dependent transcriptional signature, increased immune infiltration, and improved ICB responses. Mechanistically, DPM1 ablation reduces protein glycosylation, causing chronic IRE1 activation in cancer cells and enhanced cytotoxic T cell-mediated immunosurveillance. Inhibition or knock-out of IRE1 reverses this effect. These findings establish DPM1 as a modulator of IRE1 activity that influences tumor immunogenicity, suggesting its potential as a therapeutic target to improve cancer immunotherapy outcomes.

DOI: https://doi.org/10.1038/s41467-026-73942-z