Targeting SIRT7 offers new strategy against liver fibrosis

Liver fibrosis, a progressive scarring of the liver tissue, represents a major global health burden with limited treatment options. It is primarily driven by the activation of hepatic stellate cells (HSCs), which proliferate and secrete excess extracellular matrix proteins. Effective strategies to inactivate or eliminate these activated HSCs are crucial for reversing fibrosis. However, current therapies often lack precision and efficiency.

Recently, the team of Shao Jiangjuan/Zheng Shizhong/Cheng Haibo from Nanjing University of Chinese Medicine revealed a dual regulatory mechanism: inhibition of SIRT7 by Oroxylin A (OA) reprograms the fate of HSCs through PRMT5 succinylation-driven senescence and ecto-calreticulin (ecto-CRT)-dependent NK cell immune clearance. The study achieved a significant reduction in fibrosis markers in experimental models and highlighted the critical role of inhibiting the SIRT7 protein.

Targeting SIRT7 unlocks a dual cytotoxic and immunogenic program against activated HSCs. Natural compounds like OA offer multi-targeted therapeutic potential. Our findings reveal an efficient strategy for reprogramming HSCs fate and provide a promising candidate for anti-fibrotic therapy."

Jiangjuan Shao, lead author

Professor Shao is from the Jiangsu Key Laboratory for Pharmacology and Safety Research of Chinese Materia Media at Nanjing University of Chinese Medicine.

Dual mechanism for HSCs fate reprogramming

OA, a bioactive compound derived from the traditional Chinese herb Scutellaria baicalensis, was identified to directly bind and inhibit SIRT7, a protein highly expressed in activated HSCs. This interaction initiates a dual anti-fibrotic program: First, OA-induced SIRT7 inhibition promotes succinylation and proteasomal degradation of PRMT5, activating the cGAS-STING pathway and triggering irreversible HSCs senescence. Second, SIRT7 blockade—independent of its desuccinylase activity—leads to externalization of calreticulin (ecto-CRT) on HSCs. This "eat-me" signal facilitates recognition and elimination by NK cells via the NKp46 receptor.

Selective and recyclable anti-fibrotic effects

The researchers found that OA exhibits high selectivity for activated HSCs with good biocompatibility. The compound also demonstrated reusability and stability in its anti-fibrotic effects. In vivo experiments showed remarkable regression of liver fibrosis, supporting its therapeutic potential. The selectivity stems from specific SIRT7 targeting and subsequent immune-dependent clearance, minimizing off-target effects.

"Combatting fibrosis requires integrated manipulation of both cellular aging and immune recognition," Professor Shao said. "The complex crosstalk between HSCs and the immune microenvironment underscores the need for smart targeting strategies. Our approach provides a synergistic and sustainable solution for fibrosis treatment.