Torch, S. | bioRxiv Science

bioRxiv2025

The metabolic kinase LKB1 shapes the enteric nervous system bymitigating the oxidative stress and p53 activity

The enteric nervous system (ENS) comprises ganglia of neurons and glial cells derived from migratory multipotent neural crest cells. While the molecular mechanisms of ENS development are well-studied, the involvement of metabolic processes has received less attention. We previously showed that the tumor suppressor kinase LKB1 is essential for the trophic maintenance of postnatal ENS. Here we examined LKB1s role in ENS formation using a genetically engineered mouse model that conditionally inactivates Lkb1 in neural crest progenitors during gut invasion. We conducted a comprehensive phenotyping of the ENS through histology and 3D imaging of cleared tissue, combining lightsheet microscopy with adaptive optics confocal microscopy. We found that Lkb1 loss impairs early neuronal differentiation, followed by glial degeneration, leading to hypoganglionosis and compromised digestive tissue integrity. Metabolite profiling of digestive tracts revealed an increase of oxidative stress upon Lkb1 ablation. In vitro, Lkb1 knockdown induced oxidative stress in neural crest progenitors and their glial derivatives, causing DNA damage and p53 activation. Ablation of p53 rescued glial specification under these conditions. In vivo, hyperphosphorylation of p53 was also observed; however, deletion of p53 alleles in Lkb1 mutants did not restore enteric neurons number. Instead, it improved axonal fiber organization and partially rescued digestive tissue integrity. These findings establish LKB1 as a key metabolic regulator on both the development and maintenance of the ENS, suggesting that aberrant LKB1 signaling may contribute to human enteric glioneuropathies. HighlightsO_LILKB1 loss in enteric progenitors results in extensive hypoganglionosis and disrupts gut tissue homeostasis. C_LIO_LIDuring embryogenesis, LKB1 shapes enteric ganglia by sequentially regulating neuronal differentiation and preserving glial cells, partly by limiting oxidative stress and p53 activity. C_LIO_LIThese findings establish LKB1 as a critical regulator of neural crest cell formation, highlighting its multifaceted roles and potential pathological implications in digestive neuropathies. C_LI

developmental biology↗

bioRxiv2025

Preventing neuropathy and improving anti-cancer chemotherapy with a carbazole-based compound

Advances in cancer treatment have led to a steady increase in the rate of disease remission. However, while many treatment-related adverse effects gradually resolve after therapy, chemotherapy-induced peripheral neuropathy (CIPN) often persists, with no means of prevention or direct treatment available. Herein, we present Carba1, a novel bi-functional carbazole that mitigates neuropathy through two distinct mechanisms. First, by interacting with tubulin, Carba1 reduces the required dose of taxanes, widely used chemotherapy drugs notorious for their toxic side effects, including CIPN. Second, Carba1 activates nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in the NAD salvage pathway, triggering a metabolic rewiring that enhances the resilience of neurons and Schwann cells against chemotherapy-induced toxicity. We demonstrate the neuroprotective efficacy of Carba1 both in vitro, against neurotoxicity induced by paclitaxel (PTX), cisplatin, and bortezomib, and in vivo in a rat model of PTX-induced neuropathy. Importantly, we establish that Carba1 does not compromise the therapeutic efficacy of PTX nor promotes tumor growth. Comparative analyses of Carba1 derivatives further suggest the potential of designing compounds with either dual synergistic and neuroprotective activity or exclusive neuroprotective properties. Altogether, our findings position Carba1 as a promising therapeutic candidate for preventing CIPN, with the potential, if successfully translated to clinical settings, to improve both the quality of life and treatment outcome for cancer patients.

cancer biology↗