LSKL, Inhibitor of Thrombospondin TSP-1, is a tetrapeptide derived from Latency-Associated Protein (LAP)-TGFβ. LSKL competitively binds to and inhibits TGF-β1[1-2]. LSKL is utilized in research areas such as liver fibrosis, renal interstitial fibrosis, hydrocephalus following subarachnoid hemorrhage, and liver regeneration[3-4].
In vitro, HK-2 renal tubular epithelial cells were pretreated with LSKL (50µM) for 12 hours, followed by stimulation with OX-LDL (25µg/ml). LSKL significantly suppressed the OX-LDL-induced fibrotic response, reducing the expression of fibrosis and inflammation markers, potentially by interfering with the TGF-β pathway[5]. KYSE-150 esophageal squamous cell carcinoma cells were treated with LSKL (17.46µM). LSKL significantly reduced the cell migration and invasion induced by DJ-1 (recombinant protein) stimulation and attenuated the phosphorylation and nuclear aggregation of Smad3[6].
In vivo, in a bleomycin-induced pulmonary fibrosis mouse model, intraperitoneal injection of LSKL (4mg/kg; once daily; for 14 days) significantly alleviated bleomycin-induced intrapulmonary collagen deposition, increased hydroxyproline content, and reduced the expression of endoplasmic reticulum stress-related proteins (such as Grp78, CHOP) and fibrosis markers (such as α-SMA, fibronectin), thereby improving the fibrotic process[7]. In a streptozotocin-induced diabetic erectile dysfunction rat model, intraperitoneal injection of LSKL (30mg/kg; twice weekly; for four weeks) significantly increased the ratio of maximal intracavernous pressure to mean arterial pressure, improving erectile function, and alleviated corpus cavernosum fibrosis. LSKL reduced collagen deposition, an altered collagen I/collagen III ratio, an increased smooth muscle/collagen ratio, and decreased expression levels of thrombospondin-1, active TGF-β1, phosphorylated SMAD2/3, and collagen IV in the corpus cavernosum[8].
References:
[1] Liao F, Li G, Yuan W, et al. LSKL peptide alleviates subarachnoid fibrosis and hydrocephalus by inhibiting TSP1-mediated TGF-β1 signaling activity following subarachnoid hemorrhage in rats. Exp Ther Med. 2016 Oct;12(4):2537-2543.
[2] Song S, Shi C, Bian Y, et al. Sestrin2 remedies podocyte injury via orchestrating TSP-1/TGF-β1/Smad3 axis in diabetic kidney disease. Cell Death Dis. 2022 Jul 30;13(7):663.
[3] Zhang L, Wang C, Liu Y, et al. LSKL mitigates dehydroepiandrosterone-induced apoptosis and oxidative stress by THBS1/PI3K/AKT pathway in rat granulosa cells. Life Sci. 2026 Feb 1;386:124156.
[4] Ren R, Lu Q, Sherchan P, et al. Inhibition of Aryl Hydrocarbon Receptor Attenuates Hyperglycemia-Induced Hematoma Expansion in an Intracerebral Hemorrhage Mouse Model. J Am Heart Assoc. 2021 Oct 19;10(20):e022701.
[5] Gao L, Yang TT, Zhang JS, et al. THBS1/CD47 Modulates the Interaction of γ-Catenin With E-Cadherin and Participates in Epithelial-Mesenchymal Transformation in Lipid Nephrotoxicity. Front Cell Dev Biol. 2021 Feb 18;8:601521.
[6] Gu J, Sun Y, Song J, et al. Irradiation induces DJ-1 secretion from esophageal squamous cell carcinoma cells to accelerate metastasis of bystander cells via a TGF-β1 positive feedback loop. J Exp Clin Cancer Res. 2022 Aug 26;41(1):259.
[7] Zhan JH, Wei J, Liu L, et al. Investigation of a UPR-Related Gene Signature Identifies the Pro-Fibrotic Effects of Thrombospondin-1 by Activating CD47/ROS/Endoplasmic Reticulum Stress Pathway in Lung Fibroblasts. Antioxidants (Basel). 2023 Nov 21;12(12):2024.
[8] Xia M, Yuan Y, Fang D, et al. Blocking TSP1 Ameliorates Diabetes Mellitus-Induced Erectile Dysfunction by Inhibiting the TGF-β/SMAD Pathway. World J Mens Health. 2025 Jul;43(3):580-594.
LSKL, Inhibitor of Thrombospondin TSP-1是一种来源于潜伏相关蛋白（LAP）-TGFβ的四肽，可竞争性结合抑制TGF-β1[1-2]。LSKL可用于肝纤维化、肾间质纤维化、蛛网膜下腔出血后脑积水及肝再生等相关研究[3-4]。
在体外，LSKL（50μM）预处理HK-2肾小管上皮细胞12小时，随后在OX-LDL（25μg/ml）刺激下培养，LSKL显著抑制OX-LDL诱导的纤维化反应，降低纤维化和炎症标志物的表达，并可能通过干扰TGF-β通路发挥作用[5]。LSKL（17.46μM）处理食管鳞状细胞癌KYSE-150细胞，LSKL显著降低了由DJ-1（重组蛋白）刺激诱导的细胞迁移和侵袭能力，并减弱了Smad3的磷酸化与核聚集[6]。
在体内，在博来霉素诱导的肺纤维化小鼠模型中，腹腔注射LSKL（4mg/kg；每日一次；持续14天）可显著减轻博来霉素诱导的肺内胶原沉积、羟脯氨酸含量升高以及内质网应激相关蛋白（如Grp78、CHOP）和纤维化标志物（α-SMA、纤维连接蛋白）的表达，从而改善肺纤维化进程[7]。链脲佐菌素诱导的糖尿病性勃起功能障碍大鼠模型中，腹腔注射LSKL（30mg/kg；每周两次；持续四周）可显著提高最大海绵体内压与平均动脉压的比值，改善勃起功能，并减轻海绵体纤维化，表现为胶原沉积减少、胶原I/胶原III比值升高以及平滑肌/胶原比值升高，同时降低了海绵体内血栓反应蛋白-1、活化TGF-β1、磷酸化SMAD2/3及胶原IV的表达水平[8]。