Phloretin Attenuates Cancer Cachexia-Induced Skeletal Muscle Wasting Associated with the Modulation of STAT3 Signaling

  • Biomedicines. 2026 Apr 28;14(5):1004. doi: 10.3390/biomedicines14051004.
Kai Lin  1  2 ,  Mei-Wei He  1  2 ,  Fei Wang  1  2 ,  Xin-Yu Hu  1  2 ,  Zi-Yue He  1  2 ,  Chen-Lu Zhang  1  2 ,  Zhi-Qiang Huang  1  2 ,  Hong-Wei Wang  1  2
Affiliations
  • 1. State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Nanjing 210093, China.
  • 2. Center for Translational Medicine and Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing 210093, China.
PMID: 42193331 DOI: 10.3390/biomedicines14051004
Abstract

Background/Objectives: Cancer cachexia (CC) is a metabolic syndrome characterized by the progressive loss of skeletal muscle and adipose tissue during tumor progression. Despite its clinical prevalence, effective therapeutic options are currently lacking. Phloretin, a natural flavonoid with potent anti-inflammatory and antioxidant properties, has unclear efficacy against CC. This study investigates the therapeutic potential of phloretin in ameliorating Cancer cachexia. Methods: Mouse models of CC were established using BALB/c mice implanted with C26 colon carcinoma cells and C57BL/6 mice implanted with Lewis lung carcinoma (LLC) cells. Upon the detection of palpable tumors, phloretin (10 mg/kg) was administered daily via intraperitoneal injection. At the endpoint, hind limb skeletal muscle, inguinal white adipose tissue (iWAT), and hearts were harvested and weighed. Lean body mass was assessed by analyzing the weight of the carcass following the excision of skin, subcutaneous fat, and visceral organs. Gene expression and protein levels in muscle tissues were subsequently quantified. Results: Phloretin administration significantly alleviated tumor-induced loss of tumor-free body weight. It effectively preserved skeletal muscle mass in both C26 and LLC cachexia models, while significantly attenuating adipose tissue depletion in the C26 model. In vitro, phloretin treatment mitigated myotube atrophy induced by C26 conditioned medium. Mechanistically, phloretin inhibited STAT3 activation in skeletal muscle. This inhibition suppressed the expression of the E3 ubiquitin ligases MuRF-1 and Atrogin-1. Furthermore, phloretin concurrently modulated the Autophagy pathway. Conclusions: Phloretin effectively ameliorates Cancer cachexia-induced muscle wasting by targeting STAT3-mediated protein degradation and Autophagy pathways. These findings suggest that phloretin represents a promising therapeutic agent for the clinical management of cancer-associated cachexia.

Keywords
STAT3; cachexia; muscle atrophy; phloretin; skeletal muscle.
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