Despite the many strategies employed to slow the spread of cancer, the development of new anti-tumor drugs and the minimization of side effects have been major research hotspots in the anti-tumor field. Natural drugs are a huge treasure trove of drug development, and they have been widely used in the clinic as anti-tumor drugs. Selaginella species in the family Selaginellaceae are widely distributed worldwide, and they have been well-documented in clinical practice for the prevention and treatment of cancer. Biflavonoids are the main active ingredients in Selaginella, and they have good biological and anti-tumor activities, which warrant extensive research. The promise of biflavonoids from Selaginella (SFB) in the field of cancer therapy is being realized thanks to new research that offers insights into the multi-targeting therapeutic mechanisms and key signaling pathways. The pharmacological effects of SFB against various cancers in vitro and in vivo are reviewed in this review. In addition, the types and characteristics of biflavonoid structures are described in detail; we also provide a brief summary of the efforts to develop drug delivery systems or combinations to enhance the bioavailability of SFB monomers. In conclusion, SFB species have great potential to be developed as adjuvant or even primary therapeutic agents for cancer, with promising applications.

In this study, the extraction, purification and metabolic enzyme inhibition potential of Selaginella doederleinii were investigated. In order to extract the total biflavonoids from S. doederleinii (SDTBs), the optimum extraction process was obtained by optimizing the ultrasonic extraction parameters using response-surface methodology. This resulted in a total biflavonoid content of 22.26 ± 0.35 mg/g. Purification of the S. doederleinii extract was carried out using octadecylsilane (ODS), and the transfer rate of the SDTBs was 82.12 ± 3.48% under the optimum purification conditions. We determined the effect of the SDTBs on α-glucosidase (AG), α-amylase and xanthine oxidase (XOD) and found that the SDTBs had an extremely potent inhibitory effect on AG, with an IC₅₀ value of 57.46 μg/mL, which was much lower than that of the positive control. Meanwhile, they also showed significant inhibition of XOD and α-amylase, with IC₅₀ values of 289.67 μg/mL and 50.85 μg/mL, respectively. In addition, molecular docking studies were carried out to understand the nature of the action of the biflavonoids on AG and XOD. The results showed that robustaflavone had the lowest binding energy to AG (−11.33 kcal/mol) and XOD (−10.21 kcal/mol), while, on the other hand, amentoflavone showed a good binding affinity to AG (−10.40 kcal/mol) and XOD (−9.962 kcal/mol). Moreover, molecular dynamics simulations verified the above results.