STIM/Orai-Mediated Store-Operated Ca2+ Entry in the Pathogenesis of Fibrosis: Mechanisms and Therapeutic Opportunities

Figures

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  Figure 1. Key steps of SOCE. Agonist stimulation triggers Ca2+ release from the endoplasmic reticulum (ER) through IP3Rs and/or RyRs, leading to ER Ca2+ store depletion. STIM1 then translocates to ER–plasma membrane (PM) junctions, where it activates Orai1 channels to initiate store-operated Ca2+ entry (SOCE). The elevated cytoplasmic Ca2+ is subsequently pumped back into the ER by the SERCA pump, helping to replenish ER Ca2+ stores and sustain Ca2+ signaling through IP3Rs/RyRs. Meanwhile, Ca2+ entering through Orai1 binds to CaM, and Ca2+-bound CaM activates CN. Activated CN dephosphorylates NFAT, promoting its nuclear translocation and transcriptional activity. Abbreviations: ER, endoplasmic reticulum; IP3R, inositol 1,4,5-trisphosphate receptor; PM, plasma membrane; RyR, ryanodine receptor; SERCA, sarcoplasmic/endoplasmic reticulum Ca2+-ATPase; SOCE, store-operated Ca2+ entry; STIM1, stromal interaction molecule 1; CaM, calmodulin; CN, calcineurin; NFAT, nuclear factor of activated T cells. Figure created with BioRender.com.

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  Figure 2. Disease relevance of STIM/Orai-mediated Ca2+ signaling. Dysregulation of STIM/Orai-dependent store-operated Ca2+ entry (SOCE) contributes to diverse human diseases, including kidney injury and fibrosis [90], tubular aggregate myopathy [91], pulmonary/vascular hypertension and atherosclerosis [92,93], York platelet syndrome [94,95], type 2 diabetes-associated thrombosis [96,97], immunodeficiency/SCID [98,99], Alzheimer’s disease [17,100], and several cancers [101], including oesophageal squamous cell carcinoma [102], cervical cancer [103], and multiple myeloma [104]. Depending on the disease context, either gain or loss of STIM/Orai function alters Ca2+-dependent signaling pathways that regulate fibrosis, muscle function, platelet activation, immune responses, neuronal function, and cancer progression. Figure created with BioRender.com.

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  Figure 3. STIM1/Orai1-mediated Ca2+ signaling pathway in fibrosis. Upon endoplasmic reticulum (ER) Ca2+ store depletion, STIM1 is activated and couples to Orai1 channels at ER–plasma membrane (PM) junctions to trigger store-operated Ca2+ entry (SOCE). The resulting increase in cytoplasmic Ca2+ activates multiple downstream pro-fibrotic signaling pathways, including the CaM/MLCK axis, CaN/NFAT signaling, NF-κB activation, and the ROS–JNK/p38–SMAD3 pathway, thereby promoting myofibroblast activation and fibrotic remodeling. Abbreviations: ER, endoplasmic reticulum; TRPC1, transient receptor potential canonical 1; IP3R, inositol 1,4,5-trisphosphate receptor; SERCA, sarcoplasmic/endoplasmic reticulum Ca2+-ATPase; SOCE, store-operated Ca2+ entry; STIM1, stromal interaction molecule 1; PM, plasma membrane; CaM, calmodulin; MLCK, myosin light-chain kinase; NFAT, nuclear factor of activated T cells; NF-κB, nuclear factor kappa-B; SMAD3, SMAD family member 3; JNK, c-Jun N-terminal kinase; p38, p38 mitogen-activated protein kinase. Figure created with BioRender.com.

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  Figure 4. Small molecule regulators of the SOCE pathway, categorized into two groups: SOCE activating and SOCE blocking agents.