ALS and UPS serve key roles in DEX-induced skeletal muscle catabolism, with FoxO transcription factors serving as master regulators of both proteolytic pathways (108). DEX-induced FoxO activation promotes its nuclear translocation and leads to the upregulation of ubiquitin ligase expression, which is suppressed by FoxO knockdown (51). FoxO directly activates atrogin-1 and MuRF1 transcription by binding multiple FoxO response elements (FREs) in their promoter region rather than through indirect pathways, such as affecting their translational efficiency (19). The MuRF1 promoter contains FREs and adjacent GREs, and their interaction constitutes a key pathological mechanism underlying DEX-induced MA (93). Furthermore, atrogin-1 primarily targets regulatory proteins, such as MyoD, whereas MuRF1 is involved in the loss of MyHC induced by DEX (13,20). Notably, the FoxO regulatory network extends to other atrophy-associated ligases, including ubiquitination factor E4a (Ube4a) and muscle ubiquitin ligase of the SCF complex in atrophy-1 (MUSA1). Ube4a is a U-box-type E3 ubiquitin ligase that, in addition to catalysing substrate ubiquitination, serves as an E4 ubiquitin linker to extend the ubiquitin chain. Its expression increases in MA, whereas this increase is inhibited in the absence of FoxO (109). MUSA1, which is transcriptionally regulated by Smad and FoxO, is upregulated in various catabolic models, including MA models induced by DEX administration, denervation and fasting (91,110). Beyond canonical E3 ligases, Milan et al (91) detected a ubiquitin ligase in atrophied muscle, specific of muscle atrophy and regulated by transcription, and the expression of this enzyme exhibits FoxO dependence. Similarly, ZNF216, an A20 zinc finger-containing shuttle protein that directs ubiquitinated substrates to proteasomes, is upregulated in cells treated with DEX and transfected with constitutively active FoxO in vitro (111). FoxO directly upregulates the expression of macroautophagy- and mitochondrial autophagy-associated proteins, upregulating the mRNA expression of LC3, autophagy-related 4b (Atg4b), GABA(A) receptor-associated protein like 1 (Gabarapl1), PINK1 and parkin (17,112). FoxO indirectly participates in the regulation of autophagy in skeletal muscle through its downstream transcription factors macroautophagy and youth optimizer (MYTHO) (113) and deformed epidermal autoregulatory factor-1 (DEAF1) (114). The knockdown of MYTHO, a FoxO-dependent gene in muscle, causes autophagy dysfunction, whereas the depletion of DEAF1 promotes autophagy hyperactivation. Both of these effects lead to MA (113,114). In addition, the lysosomal protein cathepsin L, regulated by FoxO, is a mediator of DEX-induced MPB (115).

FoxO proteins indirectly regulate muscle growth factors, including Myod and Mstn (116,117), through the ALS and UPS, and directly affect their expression. FoxO exerts a dual effect on Myod regulation. Kitamura et al (118) suggested that the loss of function of FoxO1 removes the inhibitory effect on Notch signalling, resulting in the upregulation of MyoD expression. Hu et al (117) found through in vitro electrophoretic mobility shift assays and ChIP that FoxO3, but not FoxO1, binds two specific FREs in the Myod gene and activates Myod transcription by recruiting RNA pol II. Negative regulation by FoxO1 and direct activation by FoxO3 may reflect the regulation of MyoD expression by FoxO at different stages of differentiation or within specific microsignalling environments. Notably, in cachexia-induced MA, the blockade of FoxO expression concurrently elevates MyoD and decreases Mstn levels (94). The presence of five FoxO1-specific binding sites within Mstn mediates its transcriptional activation (116), and previous studies have revealed a mechanism by which Mstn drives MA by enhancing FoxO activity (119,120), suggesting that the a bidirectional positive feedback regulation process that amplifies muscle catabolic signalling. Furthermore, muscle satellite cells (MuSCs) serve a critical role in muscle injury, repair and regeneration by proliferating and differentiating into mature muscle cells to maintain muscle structure and function. FoxO1 and FoxO3 coordinate MuSC quiescence by upregulating p27^Kip1, a cell cycle inhibitor. Targeted FoxO attenuation restores MuSC proliferative capacity, thereby offering therapeutic potential for muscle regeneration and atrophy prevention (121,122).

FoxO transcription factors serve as key regulators of skeletal muscle energy homeostasis by coordinating mitochondrial biogenesis and glycolipid metabolism (17). RNA sequencing shows that following the dual knockdown of muscle insulin and IGF-1 receptors, most of the altered genes, especially those associated with mitochondrial oxidative phosphorylation (OXPHOS) and tricarboxylic acid cycle, are dependent on the regulation of FoxO (123). Mechanistically, FoxO impairs mitochondrial respiratory chain activity via the selective suppression of complex I subunit expression (124). In ageing skeletal muscle and amyotrophic lateral sclerosis models, FoxO gene deletion restores OXPHOS capacity, thereby promoting ATP synthesis (109,125). In addition, FoxO promotes the conversion of muscle metabolic substrates from glucose to lipids by regulating pyruvate dehydrogenase kinase 4 (PDK4), lipoprotein lipase and fatty acid translocase CD36 in skeletal muscle (126,127). PDK4, the most abundantly expressed isoform of PDK in skeletal muscle, inhibits pyruvate dehydrogenase complex activity via phosphorylation in the mitochondrial matrix, thereby suppressing glucose oxidation. FoxO1 binds to the PDK4 promoter region to regulate energy under starvation conditions (128). Notably, PDK4 promotes the ubiquitinated degradation of atrogin-1 by enhancing MyoG phosphorylation, which promotes DEX-induced MA (129). FoxO1 impairs systemic glucose homeostasis and promotes muscle wasting through the downregulation of glucose transporter type 4 expression in skeletal muscle (130,131) (Fig. 2).

FoxO activity regulation involves a network of PTMs and protein-protein interactions, resulting in precise functional regulation at the levels of gene transcription and protein activity. The phosphorylation, acetylation and ubiquitination of FoxO are notable post-translational modifications involved in the regulation of MA, and methylation is also a regulatory mechanism associated with MA pathogenesis (132,133). Changes in the levels of multiple PTMs of FoxO are observed in mouse and human myotubular cells following DEX treatment, suggesting DEX-induced MA may be partially mediated by altering the modification pattern of FoxO (Table I) (134). Although previous reviews have addressed FoxO regulatory mechanisms (102,103), the present review specifically focuses on MA-associated pathways and proposes targeting upstream regulators of FoxO signalling as a complementary approach to direct FoxO modulation for MA intervention.

Calissi et al (102) summarised >10 phosphokinases that regulate FoxO activity in organisms. Of these, only Akt, AMPK and mammalian sterile 20-like kinase 1 (MST1) have been specifically implicated in MA (134-137). Akt is the most important negative regulator of FoxO activity, binding FoxO to 14-3-3 proteins through phosphorylation, causing the nuclear exclusion of FoxO and inhibiting its transcriptional activity (138). This altered nuclear repulsive capacity may be associated with the charge neutralisation effect induced by Akt phosphorylation, which impairs the functionality of FoxO NLS (102). By contrast, AMPK enhances FoxO transcriptional activity through site-specific phosphorylation and interferes with the binding of FoxO to 14-3-3, thereby enhancing FoxO intranuclear stability (139). The direct substrate association between AMPK and FoxO was first established by Greer et al (140), who identified three distinct phosphorylation sites on FoxO3 following AMPK activation in mammalian cells. Each FoxO isoform contains multiple unique phosphorylation sites for Akt and AMPK, a molecular characteristic that has driven extensive investigation into the Akt/FoxO and AMPK/FoxO signalling pathways in MA (73,141). DEX suppresses Akt activity while activating AMPK in muscle; these effects promote FoxO transcription and induce MA (134). MST1 is widely expressed in muscle and important for the differentiation of C2C12 cells and its activation depends on caspase 3-mediated cleavage (142). In denervation-induced MA, MST1 enhances fast-twitch atrophy by promoting FoxO phosphorylation at Ser207, whereas MST1 knockdown attenuates this effect (137). The different functions observed under physiological and pathogenic conditions require further exploration.

In DEX-treated muscle, MA-related transcription factors (FoxO and NF-κB) are acetylated (143). The acetylation site of FoxO is primarily located in the forkhead structural domain, regulating its transcriptional activity by affecting the affinity of FoxO for DNA. FoxO acetylation exerts precise and complex effects on transcriptional activity, with activation or suppression dictated by cell type and micro-environment (144). The acetyltransferase P300 was identified as a FoxO regulator in skeletal muscle by Senf et al (145); transfection of a P300-deficient plasmid into rat skeletal muscle leads to a 4.6-fold increase in overall FoxO activity, with a 16-fold increase in FoxO3-specific activity. In a DEX-induced MA model, P300 overexpression inhibits the transcriptional activity of FoxO and differentially regulates the expression of its downstream target genes, providing a potential strategy for the treatment of MA (146). Mutants of FoxO3 have been used to verify that P300-mediated Lys262 acetylation is key for regulating FoxO3 subcellular localisation and transcriptional activity (146). HDAC1 is also a key factor regulating FoxO activity in muscle. HDAC1 overexpression (via plasmid delivery) or HDAC1 suppression (by trichostatin A) demonstrate that the deacetylation function of HDAC1 increases the activity of FoxO, its nuclear localisation, and the transcription of atrophy-related target genes. IP experiments with anti-acetylated lysine antibodies further demonstrate that FoxO is a direct target of HDAC1 deacetylation activity in muscle (147). SIRT1 is a class III HDAC and can dually regulate FoxO through deacetylation. During MA, SIRT1 directly inhibits FoxO transcriptional activity through deacetylation, a finding confirmed by luciferase reporter gene assay and ChIP (148).

Among ubiquitylated ligases reported to use FoxO as a substrate (144), only murine double minute 2 (Mdm2) has been reported in MA. In denervation-induced MA, Mdm2 expression is significantly upregulated, and its inhibition via RNA interference markedly restores FoxO3 expression (146). Mdm2 and FoxO3 form a complex, resulting in a substantial reduction in total FoxO3 protein levels (146). In addition, p300 enhances the interaction between Mdm2 and FoxO3, further promoting FoxO3 degradation (146). However, the specific sites of Mdm2 action and the contribution of this ubiquitination to MA remain to be explored.

Protein arginine methyltransferases (PRMTs) serve a key role in MuSC function and phenotypical adaptive remodelling (149). In mice, the muscle-specific depletion of PRMT1 results in decreased muscle mass and muscle weakness, accompanied by elevated levels of FoxO3 protein (133). While PRMT1 does not directly methylate FoxO3, its depletion triggers the compensatory upregulation of PRMT6 (133). PRMT6 catalyses asymmetric dimethylation at FoxO3 Arg188/Arg249 residues, inducing transcriptional hyperactivation that exacerbates autophagy and proteolysis, revealing the molecular mechanism by which PRMT1 deletion triggers MA (133).

FoxO activity is dynamically regulated by direct interaction with various proteins; such regulation influences muscle cell adaptability to atrophy-inducing stimuli. PGC-1α promotes the conversion of myofibrils into an oxidative state in skeletal muscle by regulating mitochondrial function and oxidative metabolism, thereby affecting muscle size and resistance to atrophy (74). The transfection of persistently activated FoxO3 mutants into mouse tibialis anterior muscle results in a marked decrease in muscle fibre cross-sectional area (CSA) and PGC-1α co-expression abolishes this atrophy (74). PGC-1α-mediated protection occurs via the suppression of FoxO3-driven ubiquitin ligase induction, independent of FoxO3 expression or phosphorylation changes (74,150). By contrast, Smad not only enhances the binding of FoxO3 to the MuRF1 promoter region, thereby promoting the transcriptional activity of MuRF1, but also dose-dependently increases FoxO3 protein levels by binding to specific DNA sequences in MuRF1 (151). Therefore, the combined action of Smad with FoxO may be required for the optimal activation of ubiquitin ligases. However, FoxO and Smad act independently in the regulation of Mstn expression and myoblast differentiation (116).

Quercetin is a naturally occurring flavonoid found in plants and is widely distributed in many vegetables and fruits, such as onions, apples and asparagus. It accounts for >50% of dietary flavonoid intake (152). Quercetin is a 3,3',4',5,7-pentahydroxyflavone featuring five phenolic hydroxyl groups and a conjugated double bond in its molecular structure, both of which confer powerful antioxidant activity (153). In addition, its anti-inflammatory, antiviral, anticancer and antimicrobial properties have led to a wide range of applications in dietary supplements and pharmaceutical research (154). Quercetin ameliorates DEX-induced C2C12 cell damage by scavenging ROS and restoring Δψm, highlighting its potential against MA (77). Glycosylated derivatives are the primary form of quercetin in plants, with rutin (quercetin 3-O-β-glucuronide) being the most abundant (155). In mice, rutin restores the DEX-induced weight loss of the gastrocnemius, tibialis anterior and extensor digitorum longus muscles by decreasing FoxO3 expression, thereby suppressing atrogin-1 and MuRF1-mediated protein degradation (106). In an ex vivo model, the ethanolic extract of Ricinus communis leaves alleviates DEX-induced MA by reducing oxidative stress and enhancing FoxO3 phosphorylation, which inhibits UPS-mediated MPB (156). Liquid chromatography-tandem mass spectrometry reveals that the main active component of the extract is rutin (156). In addition, the primary active ingredient of the aqueous extract of lotus leaf is a quercetin derivative, quercetin 3-O-β-glucosiduronic acid, which inhibits the expression of FoxO3 and its downstream atrophy-related genes by affecting the phosphorylation levels of AMPK and Akt, thereby increasing muscle mass in DEX-induced MA mice (157). In mice, an isoquercetin glycoside prepared from quercetin glycoside and bittersweet ameliorates the DEX-induced decrease in the gastrocnemius muscle wet weight-to-body weight ratio, as well as increasing Akt phosphorylation levels and decreasing FoxO1 content on the third day of administration (158).

Myricanol, a diarylheptanoid derived from parts of Myrica species (such as Myrica rubra bark), is a plant secondary metabolite. Although research on myricanol is limited, studies have observed multiple biological effects, including anti-inflammatory, antioxidant, apoptosis-inducing, ferroptosis-inhibiting and neuroprotective activity, in models of diseases, such as lung cancer, Alzheimer's disease and renal fibrosis (159-161). Myricetin is an AMPK activator. In zebrafish fed a high-fat diet, it effectively inhibits lipid accumulation by binding to the AMPK γ subunit (162). Shen et al (59) identified myricanol as a SIRT1 activator that directly inhibits downstream FoxO3 transcription by enhancing SIRT1 deacetylase activity, thereby alleviating DEX-induced MA and weakness. SIRT1 activation also improves autophagy and apoptosis imbalance and restores mitochondrial content/function in myotubes via the PGC-1α/FoxO3 and Akt/FoxO3 pathways (59). Given that AMPK and SIRT1 are central regulators of energy metabolism (163), myricanol is hypothesised to play a critical role in mitigating muscle metabolic dysfunction. Metabolomics analysis reveals that myricanol notably rectifies DEX-induced disturbances in glucose, lipid and protein metabolism, consequently reversing muscle mass loss and strength decline in mice (164). This effect may involve irisin secretion from myotubes, which enhances metabolic homeostasis and myogenesis (165). Recent evidence indicates that myricanol ameliorates ageing-related sarcopenia by decreasing oxidative stress (166), solidifying its status as a clinically promising candidate for regulating muscle metabolism and combating MA.

Morin, a natural pigment extracted from mulberry plants and traditional Chinese herbs, is particularly abundant in mulberry leaves. It has notable efficacy in the prevention and treatment of organ damage, neurodegenerative disease, cancer, diabetes and arthritis, primarily because of its potent antioxidant and anti-inflammatory properties (167). Morin effectively counteracts DEX-induced MA in vitro, as evidenced by increases in myotube thickness and diameter and MyHC expression (78). Moreover, it exerts antioxidant effects by inhibiting the DEX-induced upregulation of p66Shc (a redox protein) and enhancing the expression of antioxidant enzymes, such as SOD1 and catalase (78). It decreases the expression of downstream atrogenes by elevating the levels of PGC-1α and phosphorylated FoxO3 within myotubes, thereby mitigating MPB (78).

Ampelopsis grossedentata, a botanical species used in traditional Chinese medicine, is primarily employed to alleviate inflammation-related symptoms, detoxify the body, promote blood circulation and decrease phlegm. Dihydromyricetin, its predominant bioactive constituent, accounts for 30-40% of its extract (168). The bioactivities of dihydromyricetin, including its antioxidant, antimicrobial, antiviral, anti-inflammatory and antiapoptotic properties, underscore its broad therapeutic potential in disease prevention and treatment (169). Preliminary clinical validation has demonstrated its efficacy in managing metabolic-associated fatty liver disease (MAFLD) (170) and type 2 diabetes mellitus (171). Dihydromyricetin exhibits therapeutic effects in mouse models of MA induced by cisplatin and high-fat diet (172,173). In DEX-induced MA, dihydromyricetin targets PGC-1α, counteracting MA by improving Δψm, regulating mitochondrial fission-fusion dynamics and enhancing the activity of respiratory chain complexes (174). FoxO3 siRNA transfection in vitro demonstrates that dihydromyricetin suppresses atrogin-1 and MuRF1 expression via FoxO3 inactivation while restoring MyHC content via Akt/mTOR pathway activation (174).

Liquorice is one of the most widely used herbal medicines globally and is employed in traditional Chinese medicine to relieve pain, improve digestive function and alleviate cough. Glabridin, a natural isoflavonoid isolated from liquorice root extract, constitutes 0.08-0.35% of its dry weight (175). Glabridin has garnered notable attention in the cosmetics industry, accounting for 70% of patents in this field (176,177). As a potent tyrosinase inhibitor, glabridin suppresses melanogenesis, thereby exhibiting depigmentation efficacy (178). Furthermore, its antioxidant, anti-inflammatory, anticancer and antimicrobial activities have been extensively reported, providing avenues for developing drugs for treating obesity, diabetes and malignancy (179,180). Notably, glabridin serves as a phyto-oestrogen with structural and lipophilic properties analogous to those of oestradiol, suggesting its key regulatory role in bone health (181). Glabridin notably decreases MPB-related MuRF1 and CBL-B expression in C2C12 cells and mouse tibialis anterior muscle by inhibiting DEX binding to GR, blocking GR nuclear translocation and suppressing FoxO3 phosphorylation (58). Moreover, while changes in p38 phosphorylation are observed, siRNA interference reveals that p38 is not involved in the regulation of DEX-related MA (58).

Isoliquiritigenin is a natural chalcone flavonoid primarily isolated from liquorice root. This compound exhibits notable anti-inflammatory and antioxidant properties (182,183). By modulating multiple signalling pathways, including the Nrf2/HO-1, MAPK and SIRT1 pathways, it exerts notable protective effects in disease models, such as myocardial ischaemic injury, diabetic cardiomyopathy, acute kidney injury and Parkinson's disease (182,184). Isoliquiritigenin has been shown to activate the transcription factors FoxO and Nrf2, which are key regulators of cell antioxidant responses (185,186). In skeletal muscle, isoliquiritigenin has also been shown to ameliorate MA by targeting FoxO. In DEX-treated C2C12 cells and mice, isoliquiritigenin supplementation alleviates atrophic changes; specifically, it improves grip strength and exercise endurance in mice and reduces the expression of atrophy-related genes in both models (187). Isoliquiritigenin activates the Akt/mTOR signalling pathway, enhances FoxO1 and FoxO3 phosphorylation and thereby inhibits MPB and promotes MPS (187).

EGCG is the most potent catechin derivative in green tea extract, where it accounts for 50-80% of the bioactive components (188). Its 21 hydroxyl groups and stereochemical structure confer potent antioxidant activity, which manifests as chelation of metal ions and neutralisation of free radicals in redox reactions (189). Compared with other catechins, EGCG demonstrates superior biological activity, including anti-inflammatory, antiviral, antimicrobial and anticancer properties, positioning it as a promising therapeutic agent for chronic diseases, such as obesity, diabetes and cardiovascular disease (190,191). Its antitumor efficacy has progressed to clinical trials across multiple cancer types, including breast and lung cancers (192,193), with the 67 kDa laminin receptor identified as the primary mediator of its anticancer activity (194). Notably, in C2C12 cells, EGCG counteracts the DEX-induced upregulation of FoxO3 and MuRF1 via the aforementioned receptor, as evidenced by the unaltered expression observed following siRNA-mediated receptor silencing (195). High concentrations of EGCG promote the phosphorylation of FoxO3 via the activation of the PI3K/Akt signalling pathway, thereby inhibiting FoxO activation and decreasing MPB (196). Although EGCG exerts regulatory effects on multiple forms of MA through the modulation of the NF-κB, MAPK and PI3K/Akt signalling pathways (197), the molecular mechanisms underlying its protective effects against DEX-induced MA remain largely unexplored.

C7A is a flavonoid-derived catechin isolated from Ulmus macrocarpa (UM). UM, a deciduous tree predominantly distributed in China, South Korea and Japan, is traditionally utilised for treating allergic dermatoses through its root extract, while its bark exhibits therapeutic properties in skeletal health maintenance, as well as diuretic and anti-oedematous effects (198,199). UM extracts and purified C7A protect against DEX-induced MA in vitro (200). Both inhibit MPB and promote MPS by activating the Akt/mTOR signalling pathway and increasing the phosphorylation levels of FoxO1 and FoxO3 in a dose-dependent manner. Moreover, UM and C7A exhibit robust antiapoptotic properties under H₂O₂-induced muscle oxidative stress (200). Subsequent in vivo study using C57BL/6 mice confirmed the protective efficacy of UM extract (though not specifically C7A) against MA, highlighting its therapeutic potential (201).

AR, also known as linarin, is a flavonoid glycoside abundantly found in plants of the Asteraceae, Lamiaceae and Scrophulariaceae families. To the best of our knowledge, research on AR remains limited, with its anti-inflammatory, antioxidant, sedative and anti-osteoporotic activities preliminarily characterised in animal models or in vitro studies, with none having advanced to clinical investigation (202,203). Notably, molecular docking simulation has revealed that the hydroxyl groups of AR forms robust hydrogen bonding interactions with multiple residues of acetylcholinesterase (AChE), suggesting its potential as an AChE inhibitor and therapeutic candidate for Alzheimer's disease (204). The traditional herb Chrysanthemum zawadskii Herbich (CZH) exerts protective effects against DEX-induced MA by suppressing GR nuclear translocation, modulating the Akt/mTOR and FoxO3 pathways and downregulating atrogenes (205). As the most abundant bioactive constituent in CZH, AR partially mediates the aforementioned antiatrophic effects through upregulating MyoD, MyoG and MyHC expression, coupled with enhancing mitochondrial respiration in myocytes (205).

4-HD and XAG are the two primary chalcone-derived bioactive compounds isolated from Angelica keiskei (AK). Chalcones are α,β-unsaturated carbonyl compounds and serve as a biological precursor of plant flavonoids (206). Studies have characterised their anti-inflammatory properties and regulatory effects on glucose-lipid metabolism, highlighting their therapeutic potential in diabetes and obesity management (207-209). A 12-week randomised double-blind trial in obese populations demonstrated that 4-HD and XAG supplementation decrease visceral fat area and waist circumference in overweight individuals (210). Yoshioka et al (211) revealed that prolonged and acute treatment with 4-HD/XAG attenuates DEX-induced MA by inhibiting GR nuclear translocation, suppressing FoxO3 activity and downregulating ubiquitin ligase expression. Changes in the phosphorylation of p38 following 4-HD and XAG intervention are not involved in the regulation of MA (211). However, in C2C12 cells, treatment with 4-HD alone enhances myogenesis by activating the p38 signalling pathway (212). Additionally, the ethanolic extract of AK partially ameliorates DEX-induced muscle strength loss and CSA decreases, with improved effects when combined with Morus alba L. extract (141). These findings collectively suggest that the antiatrophic properties of AK are associated with its primary bioactive constituents 4-HD and XAG (Fig. 4).

Resveratrol, one of the most widely studied polyphenols, is produced by a range of plants in response to pathogen attack and participates in plant self-defence responses as an antitoxin (213,214). It is extracted from >70 plant species and is found at particularly high concentrations in grape skin and wine products (215). Evidence from human clinical trials has demonstrated resveratrol therapeutic potential across pathologies, such as Alzheimer's disease, knee osteoarthritis, and diabetic kidney disease, attributable to its pleiotropic biological activity, including antioxidant, anti-inflammatory, antitumor, antiproliferative and antiviral properties (216,217). Howitz (218) found that resveratrol mimics the effects of caloric restriction by activating SIRT1, thereby decelerating ageing. This promoted resveratrol in ageing research and facilitated its commercialisation in nutraceutical formulations (219,220). Although conclusive evidence regarding its ability to extend human lifespan remains elusive, its role as a potent SIRT1 agonist has been widely validated (216,218). It has demonstrated notable efficacy in MA treatment through SIRT1 targeting (221-224). Resveratrol alleviates MA induced by chronic kidney disease (221), ageing (222), cancer (223) and MAFLD (224) by modulating the SIRT1/FoxO1 and AMPK/SIRT1 pathways. Experimental evidence from DEX-treated L6 myotubes reveals that resveratrol suppresses FoxO1 acetylation via SIRT1 activation, consequently downregulating atrogenes, including atrogin-1 and MuRF1, at the transcriptional level (25). The introduction of SIRT1 siRNA further demonstrated that the inhibitory effect of resveratrol on DEX-induced atrogene expression in myotubes is SIRT1-dependent (25). Liu et al (73) demonstrated that the resveratrol targeting of AMPK/FoxO3 signalling not only restores DEX-impaired mitochondrial respiration but also suppresses ubiquitin ligase expression, ultimately reversing skeletal muscle mass reduction in mice. Furthermore, resveratrol exhibits notable myoprotective effects through the suppression of inflammatory cascades, oxidative insult and insulin resistance (225), making it a commonly used herb in MA treatment.

RA is a water-soluble phenolic acid compound found in culinary herbs, such as rosemary, perilla, mint, sage and other labiate plants (226). It exhibits pharmacological effects similar to those of other plant-derived NPs. These effects encompass anti-inflammatory, antioxidant, antibacterial, anticancer and immunomodulatory properties and confer potential for RA application in the pharmaceutical, food and cosmetic industries (227). Clinical evidence highlights its beneficial effects in ameliorating arthritis, cognitive impairment, allergic disorder, dermatological conditions and metabolic syndrome manifestations (228). Ethanolic extract of the traditional herb Salvia plebeia R. Br. is effective in reversing DEX-induced cell viability loss and atrogene upregulation, thereby attenuating MA progression. Centrifugal partition chromatography and high-performance liquid chromatography analyses have identified RA as a major active component in this extract (69). The coadministration of DEX with RA mitigates myotube cytotoxicity and atrophy (69). This effect is mechanistically attributed to the RA-mediated activation of the Akt/mTOR/p70S6K signalling pathway, suppression of ROS generation and apoptotic pathways, inhibition of FoxO3-mediated ubiquitin ligase expression, enhancement of autophagic flux and restoration of mitochondrial content and functionality (69).

4-CQA, a naturally occurring phenolic acid derivative, is synthesised by esterification between caffeic acid and the C4 hydroxyl group of quinic acid. This compound is abundantly distributed in Asteraceae and Lamiaceae species, where it exerts anti-inflammatory and antioxidant effects in conjunction with other quinic acid derivatives (229). 4-CQA is the predominant bioactive constituent in Peucedanum japonicum Thunb., demonstrating notable therapeutic potential against DEX-induced MA (230). In C2C12 myoblasts, 4-CQA regulates muscle protein metabolism by inhibiting the nuclear translocation of GR and FoxO3 while simultaneously activating the mTOR pathway, thereby promoting an increase in myotube diameter (230).

Trifuhalol A is a phloroglucinol compound primarily derived from the ethyl acetate extract of the edible brown alga Agarum cribrosum. By contrast with polyphenols from terrestrial plants, those from brown algae are polymers of phloroglucinol (1,3,5-trihydroxybenzene) monomers, endowing them with unique chemical structures and diverse biological activities (231). As a representative monomer, trifuhalol A has a low molecular weight and a simple structure but notable pharmacological activity, including anti-inflammatory, antiadipogenic and antidiabetic effects (232-234). Yang et al (235) reported the protective role of trifuhalol A in MA. In C2C12 cells and a zebrafish model, trifuhalol A notably improves myotube diameter and fusion index and increases muscle fibre CSA while also upregulating the locomotor capacity of zebrafish. Mechanistically, trifuhalol A inhibits protein degradation by suppressing the transcriptional activity of FoxO3, thereby downregulating the expression of its downstream targets MuRF1 and atrogin-1 (235). Concurrently, it activates the Akt/mTOR pathway and upregulates the expression of molecules such as MyoD, promoting MPS (235).

DPHC is a polyphenolic compound derived from the edible brown alga Ishige okamurae. Previous investigations have primarily focused on its therapeutic properties in inflammation suppression (236), oxidative stress mitigation (237), lipogenesis inhibition (238) and cutaneous protection (239). Compared with DEX, DPHC administration effectively prevents reductions in lean body weight, CSA and gastrocnemius muscle thickness in mice (240). These protective effects are mediated through the coordinated modulation of key signalling pathways, including the TGF-β, SIRT1, Akt, FoxO3 and Mstn pathways, which collectively decrease MPB while promoting anabolic processes (240). DPHC protects muscle tissue from DEX-induced damage by reversing the expression of the inflammatory factors IL-1β and inducible nitric oxide synthase and the antioxidant gene glutathione peroxidase 4 (240) (Fig. 5).

As members of the triterpenoid saponin family, ginsenosides are predominantly derived from plants of the genus Panax, which is used in traditional medicinal. To date, ~300 distinct ginsenosides have been isolated (241). They are classified into two primary categories on the basis of their aglycone carbon skeletons: Tetracyclic dammarane and pentacyclic oleanane types, with the former including common ginsenosides, such as Rb, Rg and Re. Ginsenosides have received extensive attention in pharmacology, as exemplified by Rg3, which achieved regulatory approval by National Medical Products Administration (NPMA) in 2000 as the first monomeric antitumor drug derived from traditional Chinese medicine (242,243). They demonstrate multifaceted therapeutic properties through the modulation of key biological processes, including cellular proliferation, apoptosis, oxidative stress, inflammation and immune regulation, thereby exhibiting clinical relevance in neurodegenerative disorder (244), cardiovascular diseases (245), ageing (246) and metabolic syndrome (247). Zha et al (248) reported that ginsenosides possess therapeutic potential for the treatment of sarcopenia by promoting muscle repair and growth: Rh1, Rg1, Rg2, Rg3 and Rg5 improve DEX-induced MA (24,249-252). Mechanistic studies have revealed that 20(S)-ginsenoside Rg3 (S-Rg3) substantially attenuates mitochondrial structural abnormality and respiratory dysfunction in a DEX-treated C2C12 in vitro atrophy model via the modulation of the AMPK/FoxO3 signalling pathway, concurrently suppressing atrogene and apoptotic protein expression (251). S-Rg3 enhances C2C12 myoblast differentiation by regulating the Akt/mTOR/FoxO3 pathway (251). This has been validated by the use of the Akt inhibitor GDC-0068 and is consistent with the findings of Men et al (24,249). Men et al (249) further demonstrated that compared with DEX, Rh1, Rg2 and Rg3 administration notably improves mitochondrial biogenesis through SIRT1/PGC-1α pathway activation.

Diosgenin, a phytosteroidal saponin, is predominantly found in fenugreek seeds and wild yam rhizomes. Its medicinal value is derived from its hypoglycaemic, hypolipidaemic, anti-inflammatory, antioxidant and immunomodulatory activity, which show notable therapeutic potential in cancer, metabolic and inflammatory disease (253). Serving as a precursor for steroid hormone synthesis, diosgenin is used in the production of hormone drugs via chemical conversion into corticosteroids, oestrogens and androgens (254). As a steroid analogue molecule, diosgenin competitively inhibits DEX and GR binding, thereby effectively mitigating DEX-induced MA (255). The antiatrophic mechanisms of diosgenin involve the upregulation of MyHC expression and suppression of ubiquitin-proteasome activity and are mediated by intracellular signalling alterations associated with GR nuclear translocation inhibition, including the modulation of Akt activation, FoxO3 Ser253 phosphorylation and P70S6K phosphorylation levels (255) (Fig. 6).

Celastrol, a pentacyclic triterpenoid predominantly isolated from the root extract of Tripterygium wilfordii, demonstrates pharmacological activities that are intrinsically linked to its functional groups, notably its C-20 carboxyl, quinone methide and C-3 hydroxyl groups. These structural features directly mediate its antimicrobial, antiproliferative, antineoplastic and cytotoxic properties (256). Celastrol exhibits broad-spectrum protective effects in in vitro and in vivo models of inflammatory disorder, obesity, diabetes mellitus and neurodegenerative diseases, establishing its status as a promising therapeutic candidate (257,258). Research has indicated that celastrol inhibits GR activity and promotes GR degradation by enhancing the interaction between GR and Ube3a (259,260). This molecular mechanism underpins its efficacy in alleviating DEX-induced MA in C2C12 myotubes. Celastrol modulates the DEX-induced downregulation of FoxO3 phosphorylation via HSP70 activation, concurrently suppressing MuRF1 expression and 26S proteasome overactivation (261). Pharmacological inhibition using tanespimycin (an HSP90 inhibitor) and U0126 (an ERK1/2 inhibitor) have revealed that the Akt/mTOR and ERK1/2 signalling pathways mediate celastrol anti-MA effects through the regulation of FoxO3 phosphorylation status (261). Celastrol exerts protective effects in an in vitro model of MA induced by doxorubicin (262).

Monotropein is a natural iridoid glycoside that is abundantly found in the root, stems and leaves of Morinda officinalis How (263). NF-κB is the most extensively studied downstream target of monotropein (264,265). Molecular docking studies have revealed that monotropein binds NF-κB, thereby inhibiting its DNA-binding activity and decreasing the expression of inflammatory factors (264,265). This anti-inflammatory action, combined with antioxidant effects, suggests monotropein may have therapeutic efficacy in osteoporosis, acute organ injury, asthma and renal cancer (266). Its antiosteoporotic effects involve oxidative stress suppression through the activation of the Akt/mTOR pathway, which contributes to MA mitigation (267,268). By modifying FoxO3 phosphorylation, monotropein-activated Akt/mTOR signalling suppresses atrogene upregulation and enhances MyHC expression in DEX-treated cells and animal (267). Therefore, focusing on the Akt/mTOR pathway may provide a molecular basis for expanding the pharmacological activity of monotropein and its potential clinical application (Fig. 7).

Fucoxanthin is abundantly distributed in algal species, particularly brown algae, accounting for ~10% of all naturally occurring carotenoids (269). As the primary photosynthetic pigment in these organisms, fucoxanthin serves as a key component of light-harvesting complexes, facilitating photon capture and energy transfer (270). Fucoxanthin is the first naturally isolated carotenoid containing an allenic bond, a structure that is hypothesised to be the basis for its multiple pharmacological effects, including anticancer, anti-obesity, antibacterial and intestinal flora regulation effects (271). The epoxy and conjugated carbonyl groups in fucoxanthin confer potent antioxidant capacity, predominantly via singlet oxygen quenching and free radical scavenging mechanisms (272). Yoshikawa et al (70) demonstrated that this antioxidative property of fucoxanthin exerts protective effects in DEX-induced MA. Compared with DEX treatment, fucoxanthin ameliorates mitochondrial dysfunction by suppressing AMPK pathway activation and markedly decreases muscular malondialdehyde and ROS. In an in vitro mechanistic study, DEX notably increased the acetylation of FoxO3 and decreased its phosphorylation in C2C12 cells (68). These effects are accompanied by a notable imbalance in ubiquitin ligase autophagy and apoptosis (68). These pathological alterations are reversed by fucoxanthin supplementation via SIRT1 pathway activation; these protective effects are attenuated by cotreatment with a SIRT1 inhibitor (68).

Astaxanthin is primarily derived from Haematococcus pluvialis, a microalgal species whose astaxanthin content accounts for 5-7% of its dry biomass, making it a key industrial source of this compound (273). Astaxanthin has better antioxidant efficacy than other carotenoids because of its oxygen-containing molecular structure (hydroxyl and ketone groups) and superior membrane permeability (274). Clinical studies have demonstrated that astaxanthin exerts beneficial effects, including neurological, cardiovascular, ocular, dermatological and immune functions, without notable adverse effects (275,276). Astaxanthin is utilised in health supplements, nutraceuticals, dermatological care and aquaculture (277,278). Additionally, astaxanthin serves as an effective sports nutrition supplement, enhancing skeletal muscle performance during exercise and mitigating adverse effects associated with muscle disuse (279). Yue et al (26) revealed that astaxanthin ameliorates DEX-induced MA. In mice, astaxanthin alleviates ubiquitination degradation, mitochondrial autophagy and glycolipid metabolism disorder and medium and high doses of astaxanthin effectively inhibit FoxO3 expression (26) (Fig. 8).

Extensive clinical trials have established that phytosterols are natural bioactive compounds capable of effectively decreasing serum cholesterol levels (280,281). A daily intake of 2.0-2.5 g lowers the risk of cardiovascular disease (280). β-sitosterol, a structural analogue of cholesterol, is one of the most abundant phytosterols and is predominantly found in plant-derived foods, such as nuts, seeds, leafy greens and vegetable oils (282). β-sitosterol is commonly incorporated into dietary supplements, particularly those targeting cardiovascular health and prostate function (283,284). Its cancer-preventive properties, attributed to its anti-inflammatory, antioxidant, proapoptotic and immunomodulatory activity, have been validated in cell assays, animal models and clinical studies (285,286). β-sitosterol has demonstrated beneficial effects on skeletal muscle mitochondrial function, biogenesis and glucolipid metabolism in multiple biological systems, including mice, C2C12 myotubes, chicken skeletal muscle (287,288). Hah et al (107) used C57BL/6 mouse and C2C12 cell models of DEX intervention to investigate the effects of β-sitosterol on skeletal muscle catabolism. Treatment with β-sitosterol ameliorates DEX-induced MA by increasing muscle mass, enhancing physical performance and suppressing MPB (107). Mechanistically, FoxO1 is a pivotal mediator of β-sitosterol catabolic inhibition, with its activation associated with the decreased expression of atrogin-1, MuRF1 and creatine kinase (107).

Stigmasterol is a common phytosterol whose chemical structure is similar to that of β-sitosterol, differing only by an additional double bond in its side chain (289). It is widely distributed in plant cell membranes, such as those of soybeans and nuts, and has analgesic, cholesterol-lowering and memory-improving properties (289). Hah et al (290) demonstrated the anti-MA effect of stigmasterol. In vivo, oral administration of stigmasterol notably reverses DEX-induced decreases in muscle mass, myofibre CSA and bone mineral density. In vitro, 10 μM stigmasterol markedly increases the diameter and fusion index of C2C12 cells, effectively ameliorating DEX-induced MA. From a molecular mechanism perspective, stigmasterol alters the subcellular distribution of FoxO3 in C2C12 cells (290). This manifests as notable inhibition of the DEX-induced nuclear accumulation of FoxO3 (290). Furthermore, stigmasterol concurrently restores mTORC1 activity, elevates the phosphorylation levels of its downstream targets p70S6K and 4EBP1 and promotes MPS in skeletal muscle (290) (Fig. 9).

Matrine, an isoquinoline alkaloid compound derived from the traditional Chinese medicinal herb ku shen, has agricultural and pharmaceutical applications (291). In agriculture, matrine is used as a low-toxicity and broad-spectrum insecticide with a good preventive effect against crop pests, such as beetles and aphids (292). In clinical practice, matrine injection has been approved by the NMPA as an adjuvant therapy to enhance chemotherapeutic outcomes in various types of cancer, including pancreatic, lung, and breast cancer (293). Mechanistically, matrine exerts its anticancer effects by inhibiting tumour cell proliferation and metastasis, inducing apoptosis and mitigating drug resistance and systemic toxicity associated with chemotherapeutic agents (294). Furthermore, its anti-inflammatory, antibacterial, antiviral, cardioprotective, neuroprotective and hepatorenal protective properties in in vitro and in vivo models have been comprehensively reviewed (293,295). The dual immunofluorescence staining of MyHC and MyoD demonstrates that matrine considerably ameliorates DEX- and TNF-α-induced MA by promoting myoblast differentiation in a dose-dependent manner (296). Treatment with 0.1-0.4 mM matrine, either alone or in combination with DEX, enhances myotube differentiation, whereas treatment with 0.4-0.8 mM matrine induces atypical myotube fusion and decreases MyoD expression (296). Mechanistically, treatment with 0.1 mM matrine for 48 h reverses the alteration of Akt/mTOR/FoxO3 pathway phosphorylation by DEX, thereby restoring the balance between protein synthesis and degradation to mitigate MA (296).

Macamides are secondary metabolites unique to maca root, with all 26 identified macamides belonging to the N-benzylamide group (297). Maca is known for its pharmacological effects on enhancing sexual function and fertility, and macamides are the primary bioactive compound mediating these benefits (298). Maca root comes in various colours, with the extract from red maca root showing the most potent muscle homeostatic modulation in promoting muscle differentiation and inhibiting MPB. An in vitro intervention experiment showed that N-(3-methoxybenzyl) linoleamide, a macamide from Lepidium meyenii, inhibits the nuclear translocation of GR and FoxO3 and downregulates MURF1 and atrogin-1 expression in a concentration-dependent manner, thereby attenuating DEX-induced MA. Molecular docking and dynamics simulation have identified multiple binding sites between MAC (18:3) and Akt1, providing mechanistic insight into its ability to enhance Akt phosphorylation during DEX challenge (299).

SA, a natural lignan extracted from the traditional herb Schisandrae fructus (SF), features a characteristic flavonoid-like core structure with four methoxy substituents (300). SA possesses diverse pharmacological properties, including anti-inflammatory, antioxidant, antineoplastic, hepatoprotective and neuroprotective activity, mediated through the modulation of multiple critical signalling pathways, such as NF-κB, Nrf2, MAPK and NLRP3 (301). SF extracts and SA exhibit therapeutic potential against DEX-induced MA. SF extract inhibits MA progression by enhancing protein synthesis in human MuSCs via the upregulation of phosphorylated (p-)4EBP1 and p-P70S6K levels (302). An in vivo experiment has revealed that SA administration reverses DEX-induced MA phenotypes in mice, as evidenced by the restoration of muscle mass, grip strength and myofibre diameter (303). SA exerts anti-MA effects by upregulating Akt, FoxO1 and P70S6K phosphorylation while suppressing atrogenes (303).

Teaghrelin, an acylated flavonoid tetraglycoside derived from oolong tea, regulates appetite and gastrointestinal function while promoting growth hormone secretion (304). Its pharmacological activity is associated with neuroprotection (305) and MA improvement (67,71). Hsieh et al (71) and Jhuo et al (67,71) demonstrated teaghrelin therapeutic efficacy against DEX-induced MA in vitro and in vivo. In C2C12 myotubes, teaghrelin mitigates DEX-induced MA by decreasing E3 ubiquitin ligase expression, maintaining MyHC levels and activating the Akt/mTOR signalling pathway (71). Teaghrelin regulates ubiquitin ligase and autophagy marker expression associated with MPB in a Sprague-Dawley rat model via Akt/FoxO1 pathway activation (67).

Sulphoraphane, an isothiocyanate abundant in Brassicaceae vegetables, including broccoli, primarily exists in plants in the form of its glucosinolate precursor glucoraphanin (306). Its clinical development as an Nrf2 activator stems from its covalent modification of Keap1 cysteine sensors, which liberates Nrf2 for activation (307). Through Nrf2/NF-κB regulation and epigenetic modification (308), sulphoraphane exhibits pharmacological activities, such as antioxidant, anti-inflammatory, antitumor and neuroprotective activity (309), and is used to treat diabetes (310). As a natural phytochemical that promotes muscle health, sulphoraphane exerts a skeletal muscle protective effect in models of muscle disease and sports injury (311,312). Sulphoraphane monotherapy at subtoxic concentrations enhances MyHCIb and MyHCIIx isoform expression levels in C2C12 myotubes without cytotoxicity (313). When DEX is co-administered with sulphoraphane, sulphoraphane promotes FoxO1 inactivation through Akt activation, leading to the effective inhibition of the DEX-induced upregulation of Mstn and atrogin-1 expression, showing a potential protective effect against MA (313) (Fig. 10).