Moreover, LRRK2 inhibition also enhances the activity of other lysosomal hydrolases. Our findings expand the understanding of the molecular mechanism of LRRK2 inhibitors, offering valuable insights for further development of PD treatments.

The medications TAE684, Cisplatin, and Midostaurin exhibited the largest negative correlation with Riskscore, according to drug sensitivity study. Lastly, we demonstrated through in vitro tests that HEATR1 knockdown markedly reduced LUAD cell survival, migration, and invasion. This study is the first to systematically integrate the ubiquitin pathway with multi-omics data, constructing a robust risk model for LUAD prognosis and immune characteristics, providing a theoretical reference for future exploration of potential biomarkers for LUAD patients' diagnosis.

In summary, our current research revealed a novel SLC34A2/LRRK2/TTF-1/SELENBP1 axis and its involvement in inhibiting the malignant characteristics of LUAD cells for the first time, which made contribution to further exploring the clinical application of SLC34A2. Furthermore, it also might offer novel insights into understanding how AT2 cells undergo malignant transformation into LUAD cells in the future.

P1, N=80, Completed, Halia Therapeutics, Inc. | Recruiting --> Completed

P2, N=650, Active, not recruiting, Biogen | Recruiting --> Active, not recruiting

P1, N=64, Recruiting, Brenig Therapeutics AU Pty Ltd. (subsidiary of Brenig Therapeutics ) | Not yet recruiting --> Recruiting

Additionally, the LRRK2 antagonist MLi-2 demonstrated remarkable efficacy in treating neurodegenerative diseases, while indazole-5-carboxamides exhibited a strong affinity for monoamine oxidases, potentially offering new therapeutic options for Parkinson's disease. Inhibition of COX-2 and FGFR resulted in anti-inflammatory effects, with minimal off-target damage observed in vivo. Collectively, our findings underscore the therapeutic versatility of indazole frameworks across various disease pathways, suggesting their potential for developing innovative treatments for cancer, infections, metabolic disorders, and neurological conditions.

P2, N=150, Recruiting, Neuron23 Inc. | Not yet recruiting --> Recruiting

P1, N=64, Recruiting, 1ST Biotherapeutics, Inc. | Not yet recruiting --> Recruiting | Trial primary completion date: Sep 2024 --> Dec 2024

P2, N=150, Not yet recruiting, Neuron23 Inc.

P2, N=50, Recruiting, Denali Therapeutics Inc. | Not yet recruiting --> Recruiting

Since PAK6 binds LRRK2 via its GTPase/Roc-COR domain and the R1441C mutation is located in the Roc domain, we used microscale thermophoresis and AlphaFold2-based computational analysis to demonstrate that PD mutations in LRRK2 affecting the Roc-COR structure substantially decrease PAK6 affinity, providing a rationale for the differential protective effect of PAK6 toward the distinct forms of mutant LRRK2. Altogether, our study discloses a novel role of PAK6 in ciliogenesis and points to PAK6 as the first LRRK2 modifier with PD mutation-specificity.