Intracellular membranes composing organelles of eukaryotes include membrane proteins playing crucial roles in physiological functions. However, a comprehensive understanding of the cellular responses triggered by intracellular membrane-focused oxidative stress remains elusive. Herein, we report an amphiphilic photocatalyst localised in intracellular membranes to damage membrane proteins oxidatively, resulting in non-canonical pyroptosis. Our developed photocatalysis generates hydroxyl radicals and hydrogen peroxides via water oxidation, which is accelerated under hypoxia. Single-molecule magnetic tweezers reveal that photocatalysis-induced oxidation markedly destabilised membrane protein folding. In cell environment, label-free quantification reveals that oxidative damage occurs primarily in membrane proteins related to protein quality control, thereby aggravating mitochondrial and endoplasmic reticulum stress and inducing lytic cell death. Notably, the photocatalysis activates non-canonical inflammasome caspases, resulting in gasdermin D cleavage to its pore-forming fragment and subsequent pyroptosis. These findings suggest that the oxidation of intracellular membrane proteins triggers non-canonical pyroptosis.

构成真核生物细胞器的细胞内膜包括在生理功能中发挥关键作用的膜蛋白。然而，对细胞内膜氧化应激引发的细胞反应的全面了解仍然难以实现。在此，我们报道了一种位于细胞内膜的两亲性光催化剂，可氧化损伤膜蛋白，导致非典型的细胞焦亡。我们开发的光催化通过水氧化产生羟基自由基和过氧化氢，在缺氧情况下会加速。单分子磁性镊子揭示光催化诱导的氧化显着破坏了膜蛋白折叠的稳定性。在细胞环境中，无标记定量揭示氧化损伤主要发生在与蛋白质质量控​​制相关的膜蛋白中，从而加剧线粒体和内质网应激并诱导裂解细胞死亡。值得注意的是，光催化作用激活非典型炎性小体半胱天冬酶，导致gasdermin D 裂解为其成孔片段并随后发生细胞焦亡。这些发现表明细胞内膜蛋白的氧化会引发非典型细胞焦亡。