Cells in metabolically active tissues with high biosynthetic and secretory demands often use robust stress-responsive mechanisms to maintain homeostasis. Coordinating such stress response mechanisms requires intercellular communication and coordination. Such modalities of intercellular communication have been relatively understudied in the context of stress tolerance. Here, we use the Drosophila melanogaster third instar fat body to demonstrate that adipocytes communicate with each other through intercellular bridges called ring canals to buffer endoplasmic reticulum (ER) stress. The fat body supports the exponential growth from embryo to late larval stage over a short period of time through its energy storage and secretory functions, enduring a high basal level of stress in the process. We discovered that individual cells in the fat body are paired to one neighboring cell through ring canals. We further demonstrate that ring canals mediate rapid and highly specific intercellular cargo and organellar trafficking, and allow the transport of cytoplasmic, ER-bound, and Golgi vesicular proteins. Disrupting fat body ring canals resulted in higher levels of stress response markers, aberrant cell size, and increased cell sensitivity and lethality in response to various exogenous stressors. We also find that animals with disrupted fat body ring canals display an overall delay in larval development, likely due to reduced secretion of larval serum proteins from the fat body. In sum, our work reveals a novel feature of intercellular communication in adipose tissue that serves to buffer stress across cells, which is required for both homeostatic secretory function and maintaining tissue viability under exogenous stress.

Hypoxia is a potent inducer of skeletal muscle atrophy; however, the underlying molecular mechanisms remain incompletely defined. Irisin, a myokine derived from Fndc5, plays a critical role in maintaining muscle mass and function, while endoplasmic reticulum (ER) stress has been implicated in muscle degeneration. Here, we investigated the interplay between hypoxia-induced ER stress and irisin regulation in skeletal muscle. Transcriptomic analyses and weighted gene co-expression network analysis (WGCNA) identified Fndc5 and Hspa5 (encoding GRP78) as key genes within hypoxia-related modules, displaying a strong negative correlation. In vivo, mice exposed to hypoxia showed reduced Fndc5/irisin expression accompanied by significant GRP78 upregulation. In vitro, chemical hypoxia and pharmacological induction of GRP78 by HA15 consistently suppressed Fndc5/irisin levels and impaired C2C12 myotube formation. Gene-miRNA network analysis suggested a shared post-transcriptional link between HSPA5-centered ER stress and FNDC5-associated atrophy programs under hypoxia, with miR-34a-5p as a candidate regulator. Collectively, these findings demonstrate that GRP78-driven ER stress under hypoxic conditions disrupts irisin production, thereby accelerating skeletal muscle atrophy. This work highlights a mechanistic axis linking ER stress to irisin deficiency in hypoxia-induced muscle wasting and provides new insights into potential therapeutic targets.

Age-dependent induction of ER stress in retinal pigment epithelium impairs phagocytosis via ADAM17-dependent MERTK shedding.

RNF26 regulating tumor immunogenicity of hepatocellular carcinoma by degrading GRP78 and instigating ER stress.

Silibinin alleviates lung fibrosis by targeting Annexin A6 to suppress endoplasmic reticulum stress and oxidative stress.

Bioinformatics analysis of signature genes associated with anoikis and endoplasmic reticulum stress in keratoconus.

The PERK-eIF2α branch activates the NLRP3 inflammasome through the NF-κB signaling pathway to suppress NDV replication.

Crebanine attenuates copper neurotoxicity via PACS-2 upregulation and TXNIP/TRPV1 axis suppression.

Effects of gallic acid on acrylamide-induced endoplasmic reticulum stress, neuroinflammation and neuronal apoptosis in rats.

PRAS40 activates the IRE1α-XBP-1-mediated unfolded protein response to exacerbate colorectal cancer by enhancing ST6Gal1-dependent α-2, 6 sialylation of GRP78.

CYR61 promotes obesity-induced kidney injury by activating endoplasmic reticulum stress.

Echinacoside regulates the IRE1/XBP1 signaling pathway through HSP72 to reduce endoplasmic reticulum stress and improve diabetic kidney disease.

Role of selenoprotein S downregulation in T-2 toxin-induced endoplasmic reticulum stress and myocardial injury.

Mangiferin improves learning and memory deficits in prenatal stress offspring through ER stress and BDNF pathway.

Qiangji Jianli Decoction attenuates skeletal muscle injury in rats with experimental autoimmune myasthenia gravis via the GRP78/IRE1α/GPX4 signaling pathway.

Cutamesine attenuates hippocampal damage via sigma-1 receptor activation following oxygen-glucose deprivation in vitro.

Atrazine increases hepatic inflammation and injury via endoplasmic reticulum (ER) stress mediated excessive formation of mitochondria-associated membranes (MAMs) and activation of the cGAS-STING pathway.

The Limb-bud and Heart (LBH) promotes renal fibrosis through endoplasmic reticulum stress-induced pyroptosis and partial epithelial-mesenchymal transition in renal tubular epithelial cells.

An osteoimmunomodulatory microneedle patch targeting ER-mitochondria calcium crosstalk for periodontal tissue regeneration.

SIRT3 promotes oxaliplatin sensitivity in hepatocellular carcinoma by promoting ferroptosis through endoplasmic reticulum stress response.