Wang Tao, Wang Mengzhou, Liu Wuming, Zhang Lin, Zhang Jia, Zhao Junzhou, Wu Zheng, Lyu Yi, Wu Rongqian
National Local Joint Engineering Research Center for Precision Surgery and Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
Int J Mol Med. 2025 Mar;55(3). doi: 10.3892/ijmm.2025.5483. Epub 2025 Jan 10.
Cold‑inducible RNA‑binding protein (CIRP) is a cold shock protein implicated in the regulation of multiple biological processes depending on its cellular localization. However, to the best of our knowledge, the role of CIRP in liver regeneration and injury after hepatectomy has not been investigated. The present study was therefore designed to explore whether CIRP is involved in liver regeneration after hepatectomy and its specific role and underlying molecular mechanism. The overall involvement of CIRP in liver regeneration and injury after hepatectomy was evaluated in CIRP‑deficient mice. C23, an antagonist of extracellular CIRP, was used to assess the effect of extracellular CIRP on liver regeneration and injury after hepatectomy. CIRP overexpression and short hairpin RNA plasmids were transfected into HepG2 cells to study the effect of intracellular CIRP on cell proliferation. The effects of extracellular CIRP on cell proliferation and injury were determined via the use of recombinant CIRP protein to stimulate HepG2 cells . The results indicated that both hepatic and serum CIRP levels significantly increased after partial hepatectomy. Additionally, CIRP deficiency impaired liver regeneration but alleviated liver injury after partial hepatectomy in mice. C23 administration attenuated liver injury and suppressed endoplasmic reticulum (ER) stress and oxidative stress. Loss‑ and gain‑of‑function analyses in HepG2 cells indicated that an increase in intracellular CIRP promoted cell proliferation via signal transducers and activation of transcription 3 (STAT3) signaling pathway activation. Moreover, recombinant CIRP had no effect on cell proliferation or STAT3 phosphorylation but induced ER stress, which was blocked by TAK242, an inhibitor of Toll‑like receptor 4 (TLR4), in HepG2 cells. Taken together, the results of the present study demonstrated that intracellular CIRP promotes liver regeneration by activating the STAT3 pathway, whereas extracellular CIRP induces ER stress possibly via the TLR4 signaling pathway after hepatectomy.
冷诱导RNA结合蛋白（CIRP）是一种冷休克蛋白，根据其细胞定位参与多种生物学过程的调节。然而，据我们所知，CIRP在肝切除术后肝脏再生和损伤中的作用尚未得到研究。因此，本研究旨在探讨CIRP是否参与肝切除术后的肝脏再生及其具体作用和潜在分子机制。在CIRP缺陷小鼠中评估了CIRP在肝切除术后肝脏再生和损伤中的总体参与情况。使用细胞外CIRP拮抗剂C23来评估细胞外CIRP对肝切除术后肝脏再生和损伤的影响。将CIRP过表达和短发夹RNA质粒转染到HepG2细胞中，以研究细胞内CIRP对细胞增殖的影响。通过使用重组CIRP蛋白刺激HepG2细胞来确定细胞外CIRP对细胞增殖和损伤的影响。结果表明，部分肝切除术后肝脏和血清中的CIRP水平均显著升高。此外，CIRP缺陷会损害肝脏再生，但可减轻小鼠部分肝切除术后的肝损伤。给予C23可减轻肝损伤，并抑制内质网（ER）应激和氧化应激。在HepG2细胞中进行的功能丧失和功能获得分析表明，细胞内CIRP的增加通过信号转导子和转录激活因子3（STAT3）信号通路激活促进细胞增殖。此外，重组CIRP对细胞增殖或STAT3磷酸化没有影响，但会诱导ER应激，在HepG2细胞中，Toll样受体4（TLR4）抑制剂TAK242可阻断这种应激。综上所述，本研究结果表明，细胞内CIRP通过激活STAT3途径促进肝脏再生，而细胞外CIRP可能在肝切除术后通过TLR4信号通路诱导ER应激。
