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Preprint WatchModerateJuly 28th, 2026

Desialylated platelets promote hepatocyte proliferation via the ERK1/2 signaling pathway

Noboruo, I.; Nakamura, T.; Okumura, M.; Nishijima, T.; Inada, H.; Tanaka, Y.; Kawaguchi, T.; Matsuoka, M.; Yasunaga, J.-i.; Uchiba, M.; Kozuma, Y.

Desialylated platelets promote hepatocyte proliferation predominantly through ERK1/2 signalling rather than JAK-STAT, through an ASGPR-independent pathway.

Moderate contradiction

1 prior failure

Two documented clinical failures match this mechanism, or a single Phase 3 failure is on record.

The preprint reports that desialylated platelets drive hepatocyte proliferation predominantly through ERK1/2 rather than JAK-STAT signalling, in an ASGPR-independent pathway. Claidex recorded ulixertinib-mapk1-erk-metastatic-uveal-melanoma-phase2-efficacy-failure on the same day, an ERK1/2 inhibitor that produced no responses in metastatic uveal melanoma. The pairing is a reminder that ERK1/2 is a shared hub with proliferative roles in normal tissue, so a systemic inhibitor is asked to separate tumour dependence from physiological signalling in liver and other regenerating tissues. Where the driver lesion is distant from ERK, as in the GNAQ and GNA11 mutant disease that trial enrolled, that separation buys nothing.

Abstract excerpt

Platelets are increasingly recognized as active regulators of tissue repair and liver regeneration beyond their classical roles in hemostasis and thrombosis. Loss of terminal sialic acid from platelet surface glycoproteins, a process known as desialylation, occurs during platelet aging or activation and has been linked to platelet clearance via the asialoglycoprotein receptor (ASGPR) on hepatocytes. However, the mechanisms by which desialylated platelets (D-plts) directly stimulate hepatocyte proliferation remain poorly understood. This study aimed to elucidate the proliferative effects of D-plts on hepatocytes and to identify the underlying signaling mechanisms. D-plts were generated and co-cultured with hepatocyte models exhibiting low or absent levels of asialoglycoprotein receptor 1 (ASGPR1) expression, including HepG2 cells, HuH-7 cells, and human chemically induced liver progenitors. Hepatocyte proliferation was assessed, and the roles of platelet-derived factors and downstream signaling pathways were investigated. Co-culture with D-plts significantly increased hepatocyte proliferation in all three cell models compared with the corresponding controls. Moreover, supernatants derived from stimulated D-plts also significantly enhanced hepatocyte proliferation, suggesting that soluble platelet-derived factors contribute to this effect. Mechanistically, the proliferative effects were mediated predominantly through the ERK1/2 signaling pathway rather than the JAK-STAT pathway in both hepatocytes co-cultured with D-plts and those treated with D-plt-derived supernatants. In conclusion, our findings demonstrate that D-plts directly promote hepatocyte proliferation through an ASGPR-independent pathway, in which ERK1/2 signaling plays a central role. These results highlight a novel mechanism through which platelet desialylation may contribute to liver regeneration.

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This is an automated contradiction flag, not an editorial judgment on the preprint's quality. Flags identify where the preclinical literature and the clinical failure record diverge.