**6. Targeting EMT Process by Molecular Docking (MD)**

MD is a promising approach for estimating the interaction between biological molecules, such as proteins and ligands [129,130]. In the last decade, MD has emerged as a promising tool in identifying lead molecules against different ailments. MD is applied to cancer stem cells (CSC) associated metabolic and signaling pathways. Different metabolic pathways participate in CSC survival concerning cancer progression and alterations [130]. This is why metabolic re-programming is considered one of the cancer symbols [131].

Natural products are considered the grounds of multi-targeting molecules. Alkaloids, a class of natural producers, are one of the promising molecules that have the strength to combat CSCs via MD [130,131]. The drugs like salasonine and tylophorine have shown that they altered the Hedgehog (Hh) pathways and exerted anti-cancer effects on CSCs [130,131]. The targeting of overexpressed receptors in cancer tissues has demonstrated anti-cancer potential by natural products earlier through MD and experimental approaches [130,131]. It is reported that natural products represent a rich source of therapeutically active compounds which can interact with numerous cellular targets and minimize the side effects [132]. MD may help us find the natural lead molecules against the EMT process. Different receptors play a role in the EMT process, so it will be more important to screen out natural compounds against those receptors to find lead molecules.

#### **7. Future Prospective**

EMT has long been suspected of contributing to cancer therapy resistance. It became clear when scientists observed strong parallels in gene expression profiles and marker expression between EMT cells and CSCs. The resistance of CSCs against pharmacotherapy is a major challenge and poses a significant threat to cancer patients. The pathways involved in EMT have been deciphered by scientists, and have developed several methodologies to investigate the phenotypes in EMT. These understandings form the basis for drug screening against EMT-mediated cancer. The miRNA and some chemical agents demonstrate inhibitory activity against EMT, but no currently available miRNAs in clinical settings can solve this problem. So natural compounds showing good results can be the game changers in mitigating the EMT process. Several small chemical agents have been discovered to help drug-resistant cancer cells targeting EMT become more chemo-sensitive. Many of these, including Ligustrazine Penisuloxazin A, Halichondramide, Sophocarpine, Fucoidan, and Diketopiperazines, were investigated in human clinical trials with standard chemotherapies or targeted treatments.

Furthermore, EMT inhibitors' long-term safety is unknown. This is especially true if EMT inhibitors activate the MET pathway, which has been linked to cancer metastasis. Moreover, studies need to be conducted to investigate the link of EMT with different pathways involved in Cancers. There is a need to develop nanoformulations targeting the cancerous to avoid off-target side effects. Moreover, with the advancement of the compounds screening assays, more novel natural compounds need to be explored to find a more potent EMT inhibitor. Novel in vitro and in vivo approaches should be developed to reduce translational failure [133].

#### **8. Conclusions**

The part of EMT-MET in cancer cell dispersion and distant metastasis has been acknowledged. Recent research suggests that EMT may not be required for cancer cell metastasis despite its importance in chemoresistance. However, this is controversial because of the EMT phenotype's variability and adaptability. Only a fraction of EMT populations may

be controlled by Fsp1. Finally, EMT is a critical cancer cell characteristic contributing to medication resistance. Inhibitors of this biological mechanism will be suitable "partners" for chemotherapy or targeted therapy medications, allowing current cancer therapies to achieve better clinical outcomes. Natural products play a dynamic role in controlling the process of EMT in cancer; many assays have been performed to prove their activity. EMT is a progression where cells can lose their epithelial properties like E-cadherin and a few more and gain mesenchymal properties like CDH2, VIM, FN1, etc. EMT has long been investigated for its involvement in cancer treatment resistance and metastasis. Assay techniques to analyze EMT phenotypic and drug screening have been created based on a better knowledge of natural chemicals and critical signaling pathways in EMT. Natural compounds that downregulate EMT phenotype and, as a result, drug resistance and metastasis have been identified, allowing scientists to discover natural compounds as EMT inhibitors capable of improving chemosensitivity of drug-resistant cancer cells while inhibiting metastasis. However, additional research is needed to fully comprehend the significance of EMT in cancer treatment resistance, cell proliferation, invasion, metastasis, and natural chemicals and their involvement in blocking EMT.

**Author Contributions:** Conceptualization: S.A. (Sirajudheen Anwar) and J.A.M.; Methodology: J.A.M. and S.A. (Sirajudheen Anwar); Software: S.A. (Sakeel Ahmed); Validation: J.A.M., S.A. (Sakeel Ahmed) and S.A. (Sirajudheen Anwar). Writing—original draft preparation: J.A.M., V.A.K. and S.A. (Sakeel Ahmed); Review and editing: S.A. (Sirajudheen Anwar), J.A., A.A. and N.A.; project administration: S.A. (Sirajudheen Anwar); Funding acquisition: S.A. (Sirajudheen Anwar). All authors have read and agreed to the published version of the manuscript.

**Funding:** This research has been funded from Research Deanship in University of Ha'il—Saudi Arabia through project number MDR-22 031.

**Institutional Review Board Statement:** Not applicable.

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** Not applicable.

**Acknowledgments:** Authors extend their appreciation to project fund from Research Deanship in University of Ha'il—Saudi Arabia through project number MDR-22 031.

**Conflicts of Interest:** Authors do not have any conflict of interest, personal or financial.

**Sample Availability:** Not applicable.

#### **References**

