SIAH2-LATS2 Axis Emerges as Promising Intervention Target in Lupus Nephritis

A breakthrough study published in the Arthritis Research & Therapy  has unveiled the therapeutic potential of Seven in Absentia Homolog 2(SIAH2)- Large Tumor Suppressor Kinase 2 (LATS2) axis, along with an exploration of protective role of vitamin K3 against lupus nephritis (LN)  fibrosis. 

Cheng et al. investigated YAP activation and LATS2 downregulation in LN kidney biopsies (LN: n = 8, normal: n = 2) and lupus prone MRL/lpr mice (n = 8 per disease stage). LATS2 function was assessed by in situ Ad-LATS2 injection in LN mice (n = 6 per group). In vivo, adenovirus-mediated restoration of LATS2 effectively reduced renal fibrotic damage in LN mice. Additionally, the investigation revealed that LATS2 degradation occurs via a K48 ubiquitination-proteasome pathway facilitated by SIAH2, thereby promoting YAP activation and exacerbating fibrosis progression in LN. Notably, the H150 region within the substrate binding domain emerged as a critical site for the interaction between SIAH2 and LATS2. Furthermore, in vivo administration of the SIAH2-specific inhibitor vitamin K3 demonstrated significant protection against LN-induced fibrotic damage. 

The SIAH2-LATS2 axis refers to the intricate molecular pathway involving the interaction between SIAH2  and LATS2. This axis plays a crucial role in regulating various cellular processes such as proliferation, apoptosis, and tissue fibrosis. Dysregulation of the SIAH2-LATS2 axis has been implicated in the pathogenesis of several diseases, including cancer and fibrotic disorders. 

LN poses a significant challenge as the most common complication of systemic lupus erythematosus, with limited treatment options that often impose heavy economic burden on patients. The progression of fibrosis in LN not only results in irreversible renal damage but also escalates to chronic kidney disease and eventually end-stage renal disease. Addressing this critical need for effective interventions, the study unveils the promising potential of targeting the SIAH2-LATS2 axis in LN, offering a beacon of hope for the development of novel treatment strategies. Furthermore, the investigation into the protective effects of vitamin K3 against LN fibrosis underscores the importance of exploring diverse therapeutic avenues to combat this debilitating condition and improve outcomes of LN patients. 

Reference 

Cheng C, Yang H, Yang C, Xie J, Wang J, Cheng L, et al. LATS2 degradation promoted fibrosis damage and rescued by vitamin K3 in lupus nephritis. Arthritis Res Ther. 2024 Mar 9;26(1):64. 

 

 

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