Inhibition of DCLK1 promotes spinal cord injury recovery: implications for KATNA1 phosphorylation in microtubule-dependent neurite outgrowth

Functional recovery after spinal cord injury (SCI) remains challenging, requiring therapeutic targets. Here, we show that doublecortin-like kinase 1 (DCLK1) is upregulated after SCI in mice. Pharmacological inhibition of DCLK1 with DCLK1-IN-1 improved motor recovery, reduced glial scar formation and fibrosis, and preserved neurons at the lesion site.

Mechanistically, we identified the microtubule-severing protein KATNA1 as a downstream target of DCLK1. DCLK1 directly phosphorylated KATNA1 at threonine 118 (T118), suppressing its microtubule-severing activity. DCLK1 overexpression inhibited, whereas DCLK1 knockdown or inhibition enhanced KATNA1 function.

The T118D mutation reduced KATNA1 activity, while T118A resisted DCLK1-mediated suppression. In neurons, DCLK1 inhibited KATNA1-induced neurite outgrowth, whereas DCLK1 inhibition restored this effect. Together, these results identify DCLK1 as a promising therapeutic target for SCI and reveal a mechanism by which DCLK1 regulates KATNA1 phosphorylation to modulate microtubule severing and neurite outgrowth.

This work was supported by the National Natural Science Foundation of China (nos. 32500880), State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University (SKLBMDA-FY25018), Guangdong Basic and Applied Basic Research Foundation (nos. 2023A1515010140, 2022A1515140169 and 2025A1515012689), Science and Technology Projects in Guangzhou (nos. 2024A03J0971, 2025A03J4235 and 2025A03J4334) and the Science and Technology Innovation Program of Hunan Province (no.2023RC3191). These authors contributed equally: Shaojin Li, Ao Ma, Changbin Lei. State Key Laboratory of Bioactive Molecules and Druggability Assessment, Department of Orthopedics, The First Affiliated Hospital of Jinan University, Guangzhou, China Shaojin Li, Ao Ma, Zhichao Meng, Jiehao Zhu, Guowei Zhang, Wei Tan & Minghui Tan Department of Orthopedics, Guangzhou Red Cross Hospital (Guangzhou Red Cross Hospital of Jinan University), Guangzhou, China Department of Orthopedics, Affiliated Hospital of Xiangnan University (Clinical College), Chenzhou, China Correspondence to Guowei Zhang, Wei Tan or Minghui Tan.

The authors declare no competing interests. All authors read and approved the final manuscript for publication. Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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