Aug 2026· Biochimica et biophysica acta. Reviews on cancer· Vol 1881, pp.
189676
· 0 citations· 123 references
Medicine
TL;DR
This review examines how tumor-derived signals activate IRE1α/XBP1 to upregulate both the autophagy-lysosome pathway (ALP) and ubiquitin-proteasome system (UPS); its crosstalk with inflammatory and metabolic networks; and the therapeutic potential of IRE1α inhibitors, XBP1-directed strategies, and nutritional approaches including arginine.
Abstract
Cancer cachexia is a multifactorial syndrome of progressive skeletal muscle wasting and functional decline that affects 50-80% of patients with advanced malignancies, frequently overlaps with sarcopenia, and contributes to 22-30% of cancer-related deaths. Effective therapies remain lacking, in part because the driving mechanisms are incompletely understood. Systemic inflammation-particularly interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α)-has long been considered central to muscle wasting, yet cytokine-targeted trials have shown limited efficacy, prompting investigation of additional pathways. Among these, endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) have emerged as candidates, and this review focuses specifically on the IRE1α/XBP1 branch. The rationale rests on three observations from recent preclinical studies: XBP1s activity is increased in cachectic muscle; XBP1s occupies regulatory regions of autophagy-lysosome and ubiquitin-proteasome genes, a direct transcriptional link to protein degradation that distinguishes it from the translation-attenuating PERK and folding-oriented ATF6 branches; and genetic or pharmacological suppression of IRE1α/XBP1 attenuates wasting in these models. We examine how tumor-derived signals activate IRE1α/XBP1 to upregulate both the autophagy-lysosome pathway (ALP) and ubiquitin-proteasome system (UPS); its crosstalk with inflammatory (JAK-STAT3, NF-κB) and metabolic (mitochondrial dysfunction, fatty acid metabolism) networks; the evidence across cancer models and clinical contexts; and the therapeutic potential of IRE1α inhibitors, XBP1-directed strategies, and nutritional approaches including arginine. We frame the ER stress-autophagy axis as a mechanistically plausible, potentially tractable therapeutic target that requires further cross-model and clinical validation.
Cisplatin is a widely used chemotherapeutic agent whose clinical utility is limited by various adverse effects. Although skeletal muscle loss during chemotherapy is often attributed to cachexia or generalized wasting, accumulating evidence indicates that cisplatin directly induces skeletal muscle atrophy. However, the underlying cellular stress responses and signaling pathways remain unclear. In this study, we investigated the involvement of endoplasmic reticulum (ER) stress and translational regulation in cisplatin-induced skeletal muscle atrophy, focusing on DNA damage-inducible transcript 4/Regulated in development and DNA damage response-1 (Ddit4/REDD1), a stress-responsive inhibitor of mammalian target of rapamycin complex 1 (mTORC1). Using a mouse model and differentiated C2C12 myotubes, we examined ER stress signaling, protein synthesis, and mTORC1 activity following cisplatin treatment, and evaluated the effects of tauroursodeoxycholic acid (TUDCA), an ER stress-suppressing chemical chaperone. Cisplatin induced skeletal muscle atrophy accompanied by ER stress activation and suppression of protein synthesis in mice. TUDCA significantly attenuated muscle mass and strength loss without affecting body weight reduction. Cisplatin upregulated ER stress-responsive genes and decreased phosphorylation of p70 S6 kinase, whereas these changes were suppressed by TUDCA. Pharmacological ER stress induction increased Ddit4/REDD1 expression, and PERK inhibition reduced cisplatin-induced Ddit4/REDD1 upregulation in C2C12 myotubes. Furthermore, Ddit4/REDD1 knockdown partially restored protein synthesis and mTORC1 signaling. These findings indicate that cisplatin induces skeletal muscle atrophy via ER stress-associated translational suppression, at least partly through Ddit4/REDD1-mediated inhibition of mTORC1.
This review integrates recent mechanistic insights into UPR-driven tumor progression, including pathway crosstalk, immune regulation, and immunotherapy resistance, with advances in small-molecule inhibitors, while critically evaluating their therapeutic potential and translational challenges in cancer treatment.
Meizhen Lin, Zhijie Li· Frontiers in Immunology· 0 citations
Obesity-associated sarcopenia (OAS) is a complex metabolic disorder characterized by excessive adiposity accompanied by progressive skeletal muscle loss, largely driven by impaired protein homeostasis. The ubiquitin-proteasome system (UPS) plays a central role in this process, with E3 ubiquitin ligases such as Atrogin-1, muscle ring-finger protein 1 (MuRF1), TNF receptor-associated factor 6 (TRAF6), and Parkin acting as key and non-redundant regulators of muscle protein degradation. Increasing evidence indicates that ginseng and its bioactive ginsenosides, including Rg1, Rb1, Rg3, and compound K, exert protective effects against multiple disease through modulation of E3-ligase dependent proteolytic pathways. In this review, we integrate emerging mechanistic insights into how ginseng-derived compounds orchestrate a polypharmacological regulatory network spanning inflammatory, metabolic, mitochondrial, and autophagic signaling axes. In particular, how ginsenosides target critical regulatory nodes, including TRAF6-mediated inflammatory amplification, Forkhead box O (FoxO)-driven transcription of Atrogin-1 and MuRF1, and Parkin-dependent mitochondrial quality control were summarized. Unlike single-target pharmacological agents, ginseng offers a multicomponent therapeutic strategy that simultaneously attenuates protein degradation while supporting anabolic signaling and mitochondrial adaptation. Nevertheless, significant translational challenges persist, including limited bioavailability, insufficient human skeletal muscle data, and poorly defined interactions among individual ginsenosides. Future research should prioritize standardized ginseng formulations and rigorously designed clinical trials to more clearly define its therapeutic potential in the management of OAS.
Wei Zhou, Pei-tong Li, Hong-Yuan Li et al.· European Journal of Pharmaco...· 0 citations
A systems-level framework is provided that transforms broad observations of inflammation into ranked therapeutic targets and support combined strategies aimed at blocking the IL-6/STAT3–myostatin/SMAD–FOXO1/3–MuRF1/Atrogin-1 axis to mitigate NSCLC-associated sarcopenia.
Gautam Kumar, Shailza Singh· Frontiers in Immunology· 0 citations
Multiple myeloma (MM) is an incurable plasma cell malignancy with limited therapeutic options. Although autophagy dysregulation is implicated in MM pathogenesis, its precise regulation, particularly by circular RNAs (circRNAs), is poorly understood. Through clinical RNA sequencing of primary MM patient samples, we identify an autophagy-associated circRNA, circ_0008255, which is markedly upregulated in MM patients and closely correlated with poor disease prognosis. Functional studies reveal that circ_0008255 promotes MM proliferation and tumor growth by enhancing autophagic activity. Mechanistically, it functions as a competitive endogenous RNA for miR-192-5p, leading to elevated expression of the core autophagy protein, autophagy related 2 homolog A (ATG2A). Furthermore, we developed a biomimetic nanoplatform based on layered double hydroxide (LDH) nanosheets coated with myeloma-derived cell membranes for tumor-specific delivery. This system co-delivers siRNA targeting circ_0008255 to suppress autophagosome initiation, while simultaneously leveraging the lysosome-alkalinizing property of LDH to impair autophagosome–lysosome fusion. Together, these actions enforce a synergistic autophagic full-chain blockade, leading to potent antitumor effects in vitro and in vivo. Overall, our study reveals a central regulatory role of circ_0008255 in myeloma autophagy, offering a promising therapeutic paradigm for MM.
Zhenhua Wang, Hefei Ren, Kun Wang et al.· Bioactive Materials· 0 citations
The tumor microenvironment (TME) is a complex ecosystem with harsh conditions, such as hypoxia, nutrient deprivation, metabolic acidosis and oxidative stress, that promote tumor progression and shape immune responses. In this environment, endoplasmic reticulum stress and the unfolded protein response are activated, with the transcription factor X-box binding protein 1 (XBP1) serving a key role. XBP1 not only maintains cell protein homeostasis, but also modulates the generation, metabolic adaptation and immunosuppressive function of myeloid-derived suppressor cells (MDSCs). The TME and tumor-derived factors, such as exosomes, remotely activate XBP1 in MDSCs, enhancing their survival and immunosuppressive capability by reprogramming lipid and glucose metabolism and upregulating the expression of arginase-1, inducible nitric oxide synthase, reactive oxygen species and immunosuppressive cytokines. The present review aimed to describe the TME stress-XBP1-MDSC-immunosuppression axis, its molecular mechanisms and the role of XBP1 in MDSC heterogeneity and plasticity. Targeting XBP1 may enhance the efficacy of existing therapies, particularly immune checkpoint blockade, by alleviating MDSC-mediated immunosuppression, offering a novel paradigm for understanding and reversing tumor immune escape.
Ziwei Chen, Jiaqi Wu, Wenxi Liu et al.· International Journal of Mol...· 0 citations