Cancer cachexia is a multifactorial wasting syndrome accompanied by an unwanted loss of body weight, primarily reflected in the loss of skeletal muscle mass with or without adipose wasting, leading to inevitable functional impairment (Baracos et al., 2018; Fearon et al., 2011; Muscaritoli et al., 2010). Cachexia occurs in more than 50% of patients with advanced cancer and causes at least 20% of cancer-related deaths (Fearon et al., 2011). In addition, patients with cancer cachexia-related muscle wasting are often experience diminished sensitivity to chemotherapy and reduced quality of life, thus shortening their survival time (Dewys et al., 1980; Wallengren et al., 2013).

At the macroscopic level, the mechanism of cancer cachexia-induced muscle atrophy involves two primary aspects: reduced food intake (anorexia) and excessive muscle wasting (Argiles, 2017). Inflammatory cell infiltration is a common feature of multiple organs and tissues during the progression of cancer cachexia (Argiles, 2017). A massive release of inflammatory factors, such as tumor necrosis factor-α (TNF-α) and interleukin (IL)-6, activates several inflammation-related signaling pathways, leading to the transcription of two E3 ubiquitin ligases, muscle-specific RING finger containing protein 1 (MuRF1) and muscle atrophy F box protein (MAFbx), that primarily mediate sarcomeric degradation (Bodine and Baehr, 2014; Foletta et al., 2011). TNF-α is a subfamily member of the TNF-like weak inducer of apoptosis. Dissociation of NF-κB p50 from the IκB complex allows the phosphorylated p50 to enter the nucleus, thereby inducing MuRF1 transcription and mediating the degradation of myosin heavy chain (MyHC) (Li and Reid, 2000; Patel and Patel, 2017). IL-6 is sufficient to induce cachexia in a CT26 tumor-bearing murine model and other models of cancer cachexia (Bonetto et al., 2012; Narsale and Carson, 2014). IL-6 mechanistically binds to the IL-6 receptor (IL-6R) or its soluble form (sIL6R), leading to the transphosphorylation and activation of Janus kinases (JAKs) and promotion of the phosphorylation and dimerization of the transcription factor signal transducer and activator of transcription 3 (STAT3), followed by translocation to the nucleus (Schaper and Rose-John, 2015; Taniguchi and Karin, 2014). Lipopolysaccharides, IL-1β, and TNF-α stimulated muscle cells to upregulate IL-6 production (Frost et al., 2002; Lang et al., 2003).

However, there is a lack of available drugs to treat cancer cachexia. Therapeutic strategies, such as nutritional support and appetite stimulants, slightly alleviate the cachexia symptoms (Donohoe et al., 2011; van der Meij et al., 2021). Monoclonal antibody drugs, such as infliximab (anti-TNFα) and clazakizumab (anti-IL6), have been designed and entered phases I and II clinical studies (Prado and Qian, 2019). However, only a few drugs have shown substantial positive effects in a larger scale phase III trial (Sousa et al., 2023; Temel et al., 2016).

There is a consensus that a combination approach may be more beneficial than a single strategy, such as nutritional supplementation or pharmacological intervention, owing to the multi-factor and multiple-target characteristics of cancer cachexia (van der Meij et al., 2021). Hence, natural products have attracted increasing interest, as they represent an essential source of biologically validated structures often used as long-term dietary supplements to ameliorate oxidative stress and inflammation. In particular, ursolic acid (UA) is a natural pentacyclic triterpenoid carboxylic acid commonly derived from plant and fruit waxes (Shanmugam et al., 2013). It possesses anti-oxidant, anti-inflammatory, and anti-cancer properties (Bang et al., 2017). Its anti-cancer activity is primarily attributed to its anti-inflammatory and chemo-protective effects, which have been extensively studied in vitro and in vivo models (Lin et al., 2013; Shanmugam et al., 2013). STAT3, NF-κB, and AKT/p70S6K signaling pathways are involved in the mediation of protein degradation and synthesis (Lin et al., 2013; Shanmugam et al., 2011). UA can improve chronic kidney disease-induced skeletal muscle atrophy, the mechanism of which is related to its inhibitory effects on myostatin and inflammatory cytokines (Yu et al., 2017). Recently, Tao et al. provided evidence that UA ameliorates Leiws lung cancer (LLC) tumor-induced skeletal muscle atrophy and elucidated the underlying mechanisms, including its regulation on the phosphorylation of NF-κB and STAT3, as well the expression of their upstream molecule SIRT1 (Tao et al., 2023). However, the therapeutic effects of UA on other models of cancer cachexia, as well as the effects and mechanisms of UA on organs and tissues other than skeletal muscle, remain to be investigated.

In this study, we used the typical CT26 tumor-bearing mice for the in vivo cancer cachexia model (Aulino et al., 2010; Chen et al., 2019) and CT26 cell culture medium-treated C2C12 myotubes for the in vitro model. The effects of UA on the skeletal muscle, heart, and intestine were investigated. In addition, the mechanism of action of UA on skeletal muscle protein degradation was determined.