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Runjie Sun,1 Jiang Liu,2 Manya Yu,1 Mengting Xia,3 Yanyu Zhang,1 Xiaoqi Sun,1 Yunsheng Xu,4 Xing Cui4 1College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, 250014, People’s Republic of China; 2Department of Foreign Affairs Office, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250014, People’s Republic of China; 3First School of Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, 250014, People’s Republic of China; 4Second School of Clinical Medicine, the Second Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250001, People’s Republic of ChinaCorrespondence: Yunsheng Xu; Xing Cui, Second School of Clinical Medicine, the Second Affiliated Hospital of Shandong University of Traditional Chinese Medicine, 1 Jingba Road, Jinan, 250001, People’s Republic of China, Email xys65@126.com; cdz45@foxmail.comBackground: Bortezomib-induced peripheral neuropathy (BiPN) is a common complication of multiple myeloma (MM) treatment that seriously affects the quality of life of patients. The purpose of the present study was to explore the therapeutic effect of paeoniflorin on BiPN and its possible mechanism.Methods: ELISA was used to measure the level of interleukin-6 (IL6) in the plasma of MM patients, and bioinformatics analysis was used to predict the mechanism underlying the effect of paeoniflorin on peripheral neuropathy. Cell and animal models of BiPN were constructed to evaluate mitochondrial function by measuring cell viability and mitochondrial quality and labeling mitochondria with MitoTracker Green. Nerve injury in mice with BiPN was assessed by behavioral tests, evaluation of motor nerve conduction velocity, hematoxylin-eosin (HE) staining, electron microscopy and analysis of the levels of reactive oxygen species (ROS). Western blotting and immunohistochemistry (IHC) were used to assess the expression of autophagy-related proteins.Results: In MM patients, IL6 levels were positively correlated with the degree of PN. The results of bioinformatics analysis suggested that paeoniflorin ameliorated PN by altering inflammation levels and mitochondrial autophagy. Paeoniflorin increased PC12 cell viability and mitochondrial autophagy levels, alleviated mitochondrial damage, and reduced IL6 levels. In addition, paeoniflorin effectively improved the behavior of mice with BiPN, relieved sciatic nerve injury in mice, increased the expression of LC3II/I, beclin-1, and Parkin in sciatic nerve cells, and increased the expression of LC3B and Parkin in the nerve tissue.Conclusion: The present study confirmed that paeoniflorin significantly ameliorated peripheral neuropathy (PN) caused by bortezomib, possibly by reducing IL6 levels to regulate PARKIN-mediated mitochondrial autophagy and mitochondrial damage.Keywords: multiple myeloma, paeoniflorin, peripheral neuropathy, mitochondria, autophagy

Introduction: N1‑methyladenosine (m1A), a methylation modification on RNA, is gaining attention for its role across diverse biological processes. However, the potential roles of m1A regulator-mediated methylation modification in multiple myeloma (MM) remain unclear.Methods: We investigated the mRNA expression of m1A regulators in normal plasma (NP, n = 9) and MM (n = 174) bone marrow plasma cells and comprehensively evaluated the m1A modification patterns of 559 MM samples based on the expression of 10 m1A-related regulatory genes. A univariate Cox regression model, Kaplan–Meier survival curve, unsupervised clustering and gene enrichment analysis were used to explore the associations between m1A‑related regulatory genes and MM patient survival and prognosis. Additionally, the m1Ascore was constructed to quantify m1A modification patterns of individual tumors using the principal component analysis algorithm.Results: Compared with NP, the expression of five genes (TRMT61A, TRMT61B, YTHDF1, YTHDF2, YTHDF3) was upregulated in MM patients. The Kaplan–Meier survival curve showed the high expression of the above five genes was associated with shorter overall survival. Three distinct m1A modification patterns were determined, of which cluster B showed the worst outcome; the expression of ALKBH3, YTHDF2, TRMT10C, TRMT6, and TRMT61B was high and the expression of ALKBH1 and YTHDC1 was low in cluster B. In addition, the relationships between the m1Ascore and survival, m1Aclusters, m1A gene clusters, and PD-L1 expression all indicated that high m1Ascore was associated with clinical benefits and therapeutic advantages.Conclusion: These findings indicate that m1A‑related regulatory genes play a crucial role in regulating MM progression and that the m1Ascore could be used for diagnostic and prognostic purposes.

Multiple myeloma (MM) secreted exosomes are essential in MM-related complications such as osteolytic bone lesions and renal failure, but their role and underlying mechanism in cardiac complications has not yet been clarified. Here, we investigated the effects of U266 (a MM cell line) exosomes (U266-exo) on regulating the viability, cell cycle, oxidative stress and apoptosis of H9C2 cells and the role of circ-CACNG2 in these effects. We found that U266-exo coculture significantly inhibited viability and promoted apoptosis of H9C2 cells, and serum exosomes of MM patients harbored high level of circ-CACNG2. The clinical data analyses indicated that circ-CACNG2 was an independent prognostic and diagnostic indicator of MM-related cardiac complications. Also, in vitro experiments showed that circ-CACNG2 inhibited viability and promoted apoptosis of H9C2 cells. RIPA, pull-down assays, dual-luciferase reporter assays, and RNA FISH assays revealed that miR-197-3p could bind to circ-CACNG2 and caspase3 directly. Rescue experiments proved that circ-CACNG2 can increase the expression of caspase3 by binding to and decreasing the expression of miR-197-3p. In conclusion, MM-exosomes could inhibit cardiomyocyte viability and promote apoptosis partially through circ-CACNG2/miR-197-3p/caspase3 axis.