LDC7559 is a novel selective inhibitor of Gasdermin D (GSDMD)[1]. GSDMD is a pore-forming protein and an executor of pyroptosis[2]. LDC7559 can antagonize the depressive effects of acrylamide (AM) and improve chronic unpredictable mild stress (CUMS) depression in mice[3].
In vitro, pretreatment of A549 cells with LDC7559 (5μM) for 6h significantly reduced the release of intracellular lactate dehydrogenase (LDH) after irradiation and increased cell survival[4]. LDC7559 (10μM) treatment of mouse melanoma B16 cells for 24h significantly inhibited VSV-CHIKV (an oncolytic virus)-induced pyroptosis, reduced the protein level of GSDMD-N (the active form of the pyroptosis executor protein), and inhibited cell membrane rupture[5].
In vivo, LDC7559 (10, 20, 30mg/kg) was intraperitoneally injected into rats with subarachnoid hemorrhage (SAH) model, which alleviated the neurological deficits after SAH, inhibited microglial activation and inflammatory response, and suppressed neuronal pyroptosis and apoptosis as well as GSDMD-mediated signal transduction[6].
References:
[1] Sollberger G, Choidas A, Burn G L, et al. Gasdermin D plays a vital role in the generation of neutrophil extracellular traps[J]. Science immunology, 2018, 3(26): eaar6689.
[2] Pandeya A, Li L, Li Z, et al. Gasdermin D (GSDMD) as a new target for the treatment of infection[J]. Medchemcomm, 2019, 10(5): 660-667.
[3] Liu J F, Han C, Shen J, et al. Acrylamide exposure promotes the progression of depression-like behavior in mice with CUMS via GSDMD-mediated pyroptosis[J]. Ecotoxicology and Environmental Safety, 2025, 289: 117443.
[4] Zhang J, Jiang Z, Liu X, et al. Regulator of G protein signaling 20 contributes to radioresistance of non-small cell lung cancer cells by suppressing pyroptosis[J]. Radiation Medicine and Protection, 2024, 5(3): 178-184.
[5] Wu F, Zhan Y, Wang S, et al. VSV-CHIKV activates antitumor immunity by inducing pyroptosis in a melanoma model[J]. Discover Oncology, 2025, 16(1): 1-15.
[6] Cai W, Wu Z, Lai J, et al. LDC7559 inhibits microglial activation and GSDMD-dependent pyroptosis after subarachnoid hemorrhage[J]. Frontiers in Immunology, 2023, 14: 1117310.
LDC7559是一种新型Gasdermin D（GSDMD）选择性抑制剂[1]。GSDMD是一种成孔蛋白，也是细胞焦亡的执行者[2]。LDC7559能够拮抗丙烯酰胺（AM）的促抑郁症作用并改善小鼠慢性不可预测轻度应激（CUMS）抑郁[3]。
在体外，LDC7559（5μM）预处理A549细胞6h，显著降低了辐照处理后细胞内乳酸脱氢酶（LDH）的释放，提高了细胞的存活率[4]。LDC7559（10μM）处理小鼠黑色素瘤B16细胞24h，显著抑制了VSV-CHIKV（一种溶瘤病毒）诱导的细胞焦亡，减少了GSDMD-N（焦亡执行蛋白的活性形式）的蛋白水平，抑制了细胞膜破裂[5]。
在体内，LDC7559（10, 20, 30mg/kg）通过腹腔注射治疗蛛网膜下腔出血（SAH）模型大鼠，缓解了SAH后大鼠的神经功能缺损，抑制了小胶质细胞活化和炎症反应，抑制了神经元焦亡和凋亡以及GSDMD介导的信号传导[6]。