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<p>Skin photodamage is closely related to mitochondrial dysfunction, and endoplasmic reticulum (ER) stress can induce excessive mitochondrial reactive oxygen species (ROS) accumulation, triggering inflammation, and inducing cell apoptosis. Polysaccharides from <i>Inonotus obliquus</i> (IOP) have antioxidant, anti-inflammatory, and immunomodulatory activities. Previous research has shown that IOP could significantly inhibit ultraviolet radiation B (UVB) induced ROS generation and apoptosis in skin cells, increase mitochondrial membrane potential and reduce the expression of ERS marker. However, the molecular mechanism has not yet been elucidated. This study used network pharmacology to analyze potential regulatory targets and explored the mechanism of IOP in alleviating UVB-induced photodamage by systematic experiments. Through network pharmacology analysis of targets related to ER, mitochondria and photodamage, it was found that core targets were concentrated in autophagy, inflammation, calcium ion (Ca<sup>2+</sup>) transport and relevant targets. Experimental results showed that Inonotus obliquus polysaccharides (IOP) significantly inhibited UVB‑induced excessive formation of cyclobutane pyrimidine dimers (CPDs) and ROS, reduced DNA damage in HaCaT cells, and thereby alleviated skin photodamage. Meanwhile, IOP inhibited the activation of the PI3K/AKT/mTOR signaling pathway, thereby enhancing the level of autophagy and alleviating mitochondrial dysfunction in UVB-irradiated HaCaT cells. Furthermore, IOP downregulated the mRNA levels of ERS markers through the PERK-eIF2α-ATF4-CHOP signaling pathway. Notably, IOP modulated the IP3R-GRP75-VDAC1 complex, which attenuated aberrant calcium transfer from ER to mitochondria and subsequent calcium overload. These coordinated effects resulted in a reduction in the expression of inflammatory cytokines and apoptotic regulators. Importantly, IOP targeted NFATc-1 to mitigate calcium dysregulation, thereby preserving ER-mitochondrial crosstalk and alleviating photodamage. Our findings underscore calcium homeostasis as a novel therapeutic approach for photoprotection and provide a support for IOP as a natural anti-photodamage agent.</p> Graphical abstract <p></p>

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Inonotus obliquus polysaccharides alleviate UVB-irradiated skin photodamage by regulating calcium homeostasis through endoplasmic reticulum-mitochondria crosstalk

  • 期刊论文

  • 发表日期：

    2026年5月7日

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  • Meng Yuan,
  • Ying-ying Zhang,
  • Xin-yue Zheng,
  • Ya-li Ru,
  • Jian-ying Chen,
  • Ze-liang Song,
  • Ning Kang,
  • Pei Lin,
  • Jun Lin

摘要

Skin photodamage is closely related to mitochondrial dysfunction, and endoplasmic reticulum (ER) stress can induce excessive mitochondrial reactive oxygen species (ROS) accumulation, triggering inflammation, and inducing cell apoptosis. Polysaccharides from Inonotus obliquus (IOP) have antioxidant, anti-inflammatory, and immunomodulatory activities. Previous research has shown that IOP could significantly inhibit ultraviolet radiation B (UVB) induced ROS generation and apoptosis in skin cells, increase mitochondrial membrane potential and reduce the expression of ERS marker. However, the molecular mechanism has not yet been elucidated. This study used network pharmacology to analyze potential regulatory targets and explored the mechanism of IOP in alleviating UVB-induced photodamage by systematic experiments. Through network pharmacology analysis of targets related to ER, mitochondria and photodamage, it was found that core targets were concentrated in autophagy, inflammation, calcium ion (Ca2+) transport and relevant targets. Experimental results showed that Inonotus obliquus polysaccharides (IOP) significantly inhibited UVB‑induced excessive formation of cyclobutane pyrimidine dimers (CPDs) and ROS, reduced DNA damage in HaCaT cells, and thereby alleviated skin photodamage. Meanwhile, IOP inhibited the activation of the PI3K/AKT/mTOR signaling pathway, thereby enhancing the level of autophagy and alleviating mitochondrial dysfunction in UVB-irradiated HaCaT cells. Furthermore, IOP downregulated the mRNA levels of ERS markers through the PERK-eIF2α-ATF4-CHOP signaling pathway. Notably, IOP modulated the IP3R-GRP75-VDAC1 complex, which attenuated aberrant calcium transfer from ER to mitochondria and subsequent calcium overload. These coordinated effects resulted in a reduction in the expression of inflammatory cytokines and apoptotic regulators. Importantly, IOP targeted NFATc-1 to mitigate calcium dysregulation, thereby preserving ER-mitochondrial crosstalk and alleviating photodamage. Our findings underscore calcium homeostasis as a novel therapeutic approach for photoprotection and provide a support for IOP as a natural anti-photodamage agent.

Graphical abstract