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PhysiologyEMBO Molecular Medicine
Peer-reviewed journal article

Targeting the canonical ER stress IRE1α/XBP1 pathway counteracts pancreatic cancer-induced skeletal muscle wasting

Aniket S. JoshiiD, Meiricris Tomaz da SilvaiD, Tuan Anh VuongiD, Bowen XuiD, Ravi Kumar SinghiD, Ashok KumariD

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Abstract

Cancer-driven cachexia is a deleterious syndrome which involves progressive loss of skeletal muscle mass with or without fat loss, fatigue, and weakness that cannot be reversed by nutritional intake. Recent studies have shown deregulation of endoplasmic reticulum (ER)-induced unfolded protein response (UPR) pathways in skeletal muscle in various catabolic conditions, including cancer growth. However, the role of individual arms of the UPR in the regulation of muscle mass remains poorly understood. Here, we demonstrate that the IRE1/XBP1 arm of the UPR stimulates the activation of ubiquitin-proteasome system, autophagy, JAK-STAT3 signaling, and fatty acid metabolism in skeletal muscle of the KPC mouse model of pancreatic cancer cachexia. Furthermore, our results show that IRE1/XBP1 pathway is a key contributor to cachexia as targeted ablation of XBP1 transcription factor in mouse skeletal muscle inhibits KPC tumor-induced muscle wasting. Transcriptionally active XBP1 protein binds to the promoter region of multiple genes, such as Map1lc3b, Fbxo32, and Il6, whose products are involved in skeletal muscle wasting. Treatment of KPC tumor-bearing mice with 4{micro}8C, a small molecule IRE1 inhibitor, reverses cachexia-induced molecular changes and improves skeletal muscle mass and strength. Altogether, our study highlights that the IRE1/XBP1 signaling axis mediates pancreatic cancer-induced muscle wasting and inhibition of this pathway could be a potential approach to mitigate muscle wasting in pancreatic cancer patients.

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In-depth summary

✦ Multi-agent verified full-text synthesis

Claude Sonnet 4.6 · xhigh effort · 8 Nov 2026 · from the full text of version 2 (4 Aug 2025) · CC BY 4.0

Muscle-specific XBP1 deletion or IRE1α inhibition with 4μ8C preserves muscle mass and strength in KPC pancreatic cachexia mice, curbing proteolysis, STAT3 signaling and fatty acid oxidation.

No therapy exists for cancer cachexia, and the role of individual unfolded protein response arms in muscle mass during pancreatic cancer cachexia was unknown. This work maps IRE1α/XBP1 as a driver of proteolysis, IL6-JAK-STAT3 signaling and fatty acid metabolism, and tests a small-molecule IRE1α inhibitor.

Key results

  1. ShownDeleting XBP1 specifically in muscle prevented KPC tumor-induced loss of tumor-free body weight, grip strength, muscle weight and myofiber size, without changing tumor weight.

    Day 21 after implantation: tumor-free body weight, grip strength and TA, GA and soleus weights fell in Xbp1fl/fl but not Xbp1mKO KPC mice (n=5 PBS, 8-9 KPC); TA and soleus CSA was higher in Xbp1mKO (n=4-5 per group); tumor weight did not differ (n=5 PBS, 9-10 KPC). · Targeted ablation of XBP1 inhibits muscle…; Figure legends

  2. ShownThe IRE1α RNase inhibitor 4μ8C, given after tumors were palpable, improved grip strength, TA and quadriceps weight and TA myofiber size in KPC mice without altering tumor growth.

    4μ8C 10mg/kg i.p. every other day from day 10, analysis day 18: normalized grip strength comparable to PBS controls; TA and Quad weight loss and TA CSA improved (CSA n=4-5 per group); tumor weight and Ki67 unchanged. · Pharmacological inhibition of IRE1α/XBP1 axis…; Figure legends

  3. ShownXBP1 loss broadly dampened the proteolytic transcriptional program in cachectic muscle, covering the ubiquitin-proteasome system and autophagy, at RNA and protein level.

    RNA-seq (Log2FC ≥ 0.25, p-value < 0.05): 152 genes up and 1558 down in KPC Xbp1mKO vs Xbp1fl/fl GA muscle; qPCR and western showed lower Fbxo32, Trim63, Map1lc3b, Becn1, ubiquitin conjugates, MAFbx, MuRF1 (n=3-4 per group). · Targeted ablation of XBP1 inhibits proteolytic…; Figure legends

  4. SuggestedSpliced XBP1 was enriched at conserved promoter motifs of catabolic genes, including its own, in KPC-CM-treated myotubes (Fbxo32, Map1lc3b, Atg5, Xbp1) and cachectic muscle (Fbxo32, Xbp1, Il6, Pdk4); IXA4 raised mRNA of several of these genes in myotubes.

    ChIP-PCR showed sXBP1 enrichment at Fbxo32, Map1lc3b, Atg5, Xbp1 in myotubes and at Fbxo32, Xbp1, Il6, Pdk4 in GA muscle, but not Stat3; n=3 biological replicates, 5 pooled mice per muscle sample. · sXBP1 directly regulates the gene expression of…; ChIP assay; Figure legends

  5. ShownThe IRE1α/XBP1 axis promoted STAT3 phosphorylation, fatty acid oxidation and protein oxidation in cachectic muscle, and STAT3 knockdown rescued myotube size under IRE1α activation.

    p-STAT3 and STAT3 were lower in KPC Xbp1mKO than Xbp1fl/fl; fatty acid oxidation rose only in KPC Xbp1fl/fl; carbonylated protein fell in Xbp1mKO; STAT3 siRNA enlarged IXA4 (20μM) myotubes; n=3-4 mice, n=3 replicates. · IRE1α/XBP1 axis regulates STAT3 signaling in…; Targeted deletion of XBP1 inhibits fatty acid…; Figure legends

Methods, data and reproducibility

Orthotopic KPC pancreatic tumor model in mice with muscle-specific Xbp1 knockout (MCK-Cre) or 4μ8C treatment; readouts were muscle mass, strength, CSA, bulk RNA-seq, qPCR, western blots, ChIP-PCR and cultured myotube assays with siRNA, 4μ8C and IXA4.

  • Orthotopic KPC tumor-bearing wild-type, Xbp1fl/fl and Xbp1mKO mice (2 x 10^5 KPC cells; Fig. 1 and Fig. 2 cohorts male) vs PBS controls; muscle phenotyping and molecular assays · mouse · n = n=5 PBS and 8-9 KPC (Fig. 2A-C); n=3-5 or 9-10 elsewhere
  • Bulk RNA-seq of gastrocnemius muscle from PBS- or KPC-injected Xbp1fl/fl and Xbp1mKO mice (NextSeq550, 75 base paired-end) · mouse · PRJNA1255232
  • Primary myotube cultures treated with KPC conditioned medium, XBP1 or STAT3 siRNA, 4μ8C or IXA4; ChIP-PCR and diameter assays · mouse · n = n=3 biological replicates per group
Methods & tools
CLC Genomics Workbench 20, Metascape, GSEA, TRRUST database, UCSC genome browser, R v 4.2.2 (ggplot, heatmap.2), ImageJ, 4μ8C (IRE1α RNase inhibitor), IXA4 (IRE1α activator), SimpleChIP enzymatic chromatin IP kit, OxyBlot protein oxidation kit, Illumina NextSeq550
Reagents & environment
CLC Genomics Workbench 20 with Biomedical Genomics Analysis Plugin 20.0.1; mouse reference Refseq GRCm39.105; R software v 4.2.2.
Reproducibility gaps
No analysis code repository reported. Raw RNA-seq files are said to be in NCBI SRA (PRJNA1255232); primer sequences and antibodies are in supplementary tables.
Limitations (5)
  • Findings come from one KPC orthotopic model; whether similar mechanisms operate in other cachexia models and in pancreatic cancer patients remains to be determined. · stated by the authors
  • 4μ8C modestly reduced KPC cell numbers by day 5 in culture, so dosing began on day 10 to separate muscle effects from tumor effects; the role of the pathway in cancer cell survival and chemotherapy response is unresolved. · stated by the authors
  • The contribution of XBP1-driven ERAD to muscle wasting was only inferred from RNA-seq and was not tested functionally. · stated by the authors
  • Many assays use small groups (n=3-4 mice or 3 replicates), the knockout and tumor-characterization cohorts were male, and the muscle ChIP-PCR used pooled mice, which limits statistical power and generalizability. · noted in this summary
  • 4μ8C did not restore tumor-free body weight, and it also blocks RIDD, so the pharmacological benefit cannot be attributed to XBP1 splicing alone. · noted in this summary

Who should read:Read this if you study cancer cachexia, ER stress signaling in muscle, or want preclinical evidence for IRE1α inhibition as a muscle-sparing strategy in pancreatic cancer.

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