Nintedanib induces senolytic effect via STAT3 inhibition

Area of Science:

• Cellular Senescence
• Aging Research
• Pharmacology

Background:

• Selective removal of senescent cells (senolytic therapy) is a promising strategy for age-related diseases.
• Existing senolytic agents like ABT263 induce apoptosis via intrinsic pathways.
• Understanding novel senolytic mechanisms is crucial for expanding therapeutic options.

Purpose of the Study:

• To investigate nintedanib, a tyrosine kinase inhibitor, as a potential senolytic agent.
• To elucidate the mechanism of nintedanib-induced senescent cell death.
• To evaluate nintedanib's efficacy in preclinical models of aging and fibrosis.

Main Methods:

• Treatment of primary human dermal fibroblasts and human pulmonary fibroblasts with nintedanib.
• Assessment of apoptosis, cell cycle arrest, and protein levels (Bcl-2 family, JAK2/STAT3 pathway).
• Evaluation in a mouse model of bleomycin-induced lung fibrosis.

Main Results:

• Nintedanib selectively induced apoptosis in senescent cells, similar to ABT263, but via a distinct mechanism.
• Nintedanib caused G1 cell cycle arrest in non-senescent cells without cytotoxicity.
• Nintedanib suppressed JAK2/STAT3 activation, and STAT3 inhibition promoted senescent cell death; it reduced senescent cells and fibrosis in vivo.

Conclusions:

• Nintedanib is identified as a novel senolytic agent with a unique mechanism involving JAK2/STAT3 inhibition.
• Inhibiting the STAT3 pathway presents a viable strategy for inducing selective senescent cell death.
• Nintedanib holds potential for treating aging conditions and age-related diseases like lung fibrosis.