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Targeting TLR2/Rac1/cdc42/JNK Pathway to Reveal That Ruxolitinib Promotes Thrombocytopoiesis

Background: Thrombocytopenia has long been considered an important complication of chemotherapy and radiotherapy, which severely limits the effectiveness of cancer treatment and the overall survival of patients. However, clinical treatment options are extremely limited so far. Ruxolitinib is a potential candidate.

Methods: The impact of ruxolitinib on the differentiation and maturation of K562 and Meg-01 cells megakaryocytes (MKs) was examined by flow cytometry, Giemsa and Phalloidin staining. A mouse model of radiation-injured thrombocytopenia (RIT) was employed to evaluate the action of ruxolitinib on thrombocytopoiesis. Network pharmacology, molecular docking, drug affinity responsive target stability assay (DARTS), RNA sequencing, protein blotting and immunofluorescence analysis were applied to explore the targets and mechanisms of action of ruxolitinib.

Results: Ruxolitinib can stimulate MK differentiation and maturation in a dose-dependent manner and accelerates recovery of MKs and thrombocytopoiesis in RIT mice. Biological targeting analysis showed that ruxolitinib binds directly to Toll Like Receptor 2 (TLR2) to activate Rac1/cdc42/JNK, and this action was shown to be blocked by C29, a specific inhibitor of TLR2.

Conclusions: Ruxolitinib was first identified to facilitate MK differentiation and thrombocytopoiesis, which may alleviate RIT. The potential mechanism of ruxolitinib was to promote MK differentiation via activating the Rac1/cdc42/JNK pathway through binding to TLR2.

Comments：

Based on the methods and results you have provided, it seems that ruxolitinib has a positive effect on the differentiation and maturation of megakaryocytes, as well as accelerating recovery of thrombocytopoiesis in mice with radiation-injured thrombocytopenia.

The use of network pharmacology, molecular docking, and other molecular and protein analysis techniques helped to identify the potential mechanism of action of ruxolitinib. It appears that ruxolitinib may activate the Rac1/cdc42/JNK pathway by binding directly to Toll Like Receptor 2 (TLR2), leading to MK differentiation and maturation.

Overall, these findings suggest that ruxolitinib may have potential as a therapeutic option for thrombocytopenia in cancer patients undergoing chemotherapy and radiotherapy. Further research is needed to fully understand the safety and efficacy of this treatment approach, but this study provides important insights into the potential mechanisms underlying ruxolitinib's actions.

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S6597 TLR2-IN-C29 TLR2-IN-C29 (C29) is a Toll-like receptor 2 (TLR2) inhibitor that inhibits TLR2/1 and TLR2/6 signaling.

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