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Abstract Background Shenqi Compound (SQC) has been used in clinic for several decades in the prevention and treatment of diabetes and its complications. But this is merely a heritage of experience. The primary aim of this study is to scientifically validate the therapeutic effects of SQC on diabetic vascular calcification (DVC) in an animal model and, simultaneously, uncover its potential underlying mechanisms. Method Spontaneous diabetic rat- Goto Kakizaki (GK) rats were selected for rat modeling. We meticulously designed three distinct groups: a control group, a model group, and an SQC treatment group to rigorously evaluate the influence of SQC. Utilizing a comprehensive approach that encompassed methods such as pathological staining, western blot analysis, qRT-PCR, and RNA sequencing, we thoroughly investigated the therapeutic advantages and the underlying mechanistic pathways associated with SQC in the treatment of DVC. Result The findings from this investigation have unveiled the extraordinary efficacy of SQC treatment in significantly mitigating DVC. The underlying mechanisms driving this effect encompass multifaceted facets, including the restoration of aberrant glucose and lipid metabolism, the prevention of phenotypic transformation of vascular smooth muscle cells (VSMCs) into osteogenic-like states, the subsequent inhibition of cell apoptosis, the modulation of inflammation responses, the remodeling of the extracellular matrix (ECM), and the activation of the Hippo-YAP signaling pathway. Collectively, these mechanisms lead to the dissolution of deposited calcium salts, ultimately achieving the desired inhibition of DVC. Conclusion Our study has provided compelling and robust evidence of the remarkable efficacy of SQC treatment in significantly reducing DVC. This reduction is attributed to a multifaceted interplay of mechanisms, each playing a crucial role in the observed therapeutic effects. Notably, our findings illuminate prospective directions for further research and potential clinical applications in the field of cardiovascular health. Graphical Abstract

Autophagic flux blockade and excessive oxidative stress play important roles in the pathogenesis of diabetic vascular calcification (VC). Transcription factor EB (TFEB) is an important regulator of many autophagy-lysosomal related components, which is mainly involved in promoting autophagy process in cells. Nuclear factor erythroid-2 related factor 2 (Nrf2) antioxidant system is considered as one of the key pathways in response to intracellular oxidative stress. Periostin (POSTN), a matrix protein, is widely involved in regulating the formation and maintenance of organs such as bones, teeth, heart valves, and tendons. We have previously reported that POSTN interfered with autophagic flux in an oxidative stress-dependent manner in vascular smooth muscle cells (VSMCs) to aggravate the development of diabetic VC. However, how POSTN interfered with autophagic flux by regulating oxidative stress has not been clarified. This study aims to further explore the roles of TFEB, POSTN, autophagy and Nrf2 antioxidant system in the development of diabetic VC. Our experimental results revealed that activation of TFEB attenuated diabetic VC by improving autophagic flux and activating Nrf2 antioxidant system, while POSTN reduced the autophagic degradation of KEAP1 by inhibiting lysosomal function, thus inhibiting the activation of the Nrf2 antioxidant system, and ultimately abolishing the protective effect of TFEB against diabetic VC. In conclusion, this study uncovers that TFEB play an important role in alleviating diabetic VC by improving autophagic flux and activating Nrf2 antioxidant system, suggesting that TFEB may be a new target for the prevention and treatment of diabetic VC.