All eukaryotic cells possess an adaptive ability known as autophagy, a process which conserves evolution, leading to the internal break-down of proteins with longer lives and organelles, including mitochondria, that tend to become firm [1]. Cellular autophagy is a fundamental response to stress that escalates rapidly due to variations in deprivation, including inadequate nutrition, energy, and growth factors, oxygen deficiency, difficulties with the endoplasmic reticulum, and the presence of intracellular pathogens or toxins [2]. When environmental conditions necessitate it, certain structures inside of the cell undergo autophagy, a process that breaks down large molecules into their most basic components (like proteins being turned into amino acids). This allows the parts of the cell to be recycled and reused. What is more, autophagy has been found to single out some proteins, organelles, and even RNAs for destruction, confirming its fundamental role in forming the arrangement of a cell. Despite this, it has been observed on occasion that the initiation of autophagy is linked to cellular demise [3], [4]. Consequently, it is very important to ensure that autophagy is regulated accurately within cells. Autophagy can occur in a non-discriminative manner or in a specific manner. The former process involves encapsulating sections of the cytoplasm and transporting them to lysosomes to be destroyed. The latter, selective autophagy, focuses on recognizing and eliminating specific objects such as damaged parts of the cell, protein accumulation, and infectious agents. Studies have recently indicated that an inappropriate level of autophagy can result in genomic destruction, metabolic strain, and tumor formation [5]. A variety of research reveals that autophagy has had connections to both beginning and treating cancer for an extensive period of time [6], [7]. Studies suggest that autophagy could be integral in controlling the activity of genes that can cause or prevent cancer growth [8]. Studies have suggested that autophagy may have either a positive or negative influence on the formation of cancer, as well as its ability to promote tumor growth [9]. Aside from tumor, flaws in autophagy have been associated with a variety of medical issues including muscle issues [10], pathogen infections (Listeria monocytogenes) [11], cerebral ischemia [12], neurodegeneration [12], [13], [14], psychiatric disorders [15], [16], [17], viral infection [18] and more.

Many believe autophagy plays a major part in fighting tumors. While chemo has helped a large number of people successfully, acquired drug resistance has become a big issue in terms of treatment effectiveness. Different research has indicated that numerous chemotherapeutic drugs can bring on autophagy [19]. Additionally, autophagy appears to be associated with chemotherapy resistance in tumors. While chemotherapy may successfully lead to apoptosis in cancer cells, the cells can frequently activate autophagy to defend themselves from the treatment, decreasing the potency of the chemotherapy.

Small pieces of RNA measuring between 20 and 23 nucleotides in length which do not possess the ability to manufacture proteins are known as microRNAs. They act by connecting to a specific mRNA molecule, stopping it from being translated to protein or making it degradable [20], [21], [22]. By doing so, they are critical controllers of countless cellular processes and bodily functions, such as autophagy, the development of the cell cycle, cellular replication, and apoptosis [23], [24], [25]. miRNA attachment to the 3’ UTR of mRNAs causes either the destruction of the designated mRNA or the prevention of its translation into the necessary protein [21], [26], [27], [28], [29]. Autophagy is not an exception when it comes to its involvement in cellular irritation and endurance reactions; the genetics and proteins related to the autophagy pathways are controlled by numerous miRNAs, otherwise called autophagy-controlling miRNAs or autophagomirs. These miRNAs were first discovered in 2009 with the original identification of MIR30A. Since then, there has been an accelerated advancement in comprehending miRNAs' role in autophagy, yet the knowledge is still very much in its early stages. Recent research has demonstrated the intricate web of miRNAs that control autophagy during normal conditions, and has suggested that the misregulation of autophagomirs could be linked to ailments such as cancer, neurodegeneration, cardiovascular disease, and infections. Exosomal microRNAs have been discovered to be a fundamental part of controlling autophagy and related conditions [18], [30], [31]. As an illustration, research has revealed that exosomes that originate from bone marrow mesenchymal stem cells can stimulate autophagy in cervical cancer cells by decreasing the miR-21 concentration. In this review, the chief emphasis shall be on the performance of miR-21 in cancer cell autophagy as well as miR-21/exosomes in drug resistance in autophagy. Additionally, investigators will ponder how exosomal miR-21 affects autophagy, and how miR-21 could be utilized to command autophagy in noncancerous ailments.

Humans encode a gene known as miR-21, which is responsible for creating mature miR-21. To start, the primary transcript, pri-miR-21, is produced by RNA polymerase II inside the nucleus. This is followed by two successive processes to form the fully mature miR-21. To create pre-miR-21, a stem-loop structure of almost 72 nucleotides, the Drosha enzyme from the RNA polymerase III family and the DiGeorge syndrome critical region 8 (DGCR8) coenzyme collaborate [32]. Exportin 5 serves to enable the conveyance of pre-miR-21 from the nucleus to the cytoplasm, where the RNA polymerase III family's Dicer enzyme executes further processing of the molecule. This enzyme causes the production of a pair of molecules composed of miRNA*, which typically consists of molecules that are strongly resilient and hard to separate. In contrast, due to being less stable, miRNA molecules are simpler to unpick and couple with the RNA-induced silencing complex (RISC). The result of this union of the miRNA and the miRNA* is referred to as miRISC, which then connects to the 3′ UTR of a particular mRNA, helping to alter gene expression [33], [34].

The miR-21 gene is specific to humans and can be found at q23.1 on chromosome 17 right next to the Vacuole Membrane Protein-1 (VMP1) gene. This gene is part of exon 10 of VMP1. Every species has its own unique miR-21 gene [35]. The phenomenon of miR-21 expression could potentially be regulated by a range of transcribing proteins, which include AP-1, Ets/PU.1, C/EBPα, NF-I, SRF, p53, and STAT3 [36], [37], [38], [39]. Different transcription factors control the expression of miR-21 through a variety of pathways. Studies have indicated that inducing activation of AP-1 containing PU.1 in 293FT cells escalates the amount of miR-21 being transcribed. Oppositely, the functioning of NFIB and C/EBPα in tandem produces a drop in the levels of miR-21, establishing a back-and-forth regulation between the two [40]. In the context of multiple myeloma, STAT3 transcription factor is responsible for switching on the enhancer that is responsible for the control of miR-21, while IL-6 cytokine sets off the process of miR-21 transcription [41].

In addition to regulatory control at the transcriptional level, posttranscriptional restrictions influence the production of miR-21 as well. Transforming growth factor-β (TGF-β) and bone morphogenetic protein 4 (BMP4) can intensify the activity of primary transcripts of miR-21 when those proteins receive instructions from the Drosha protein [42]. Furthermore, the amount of miR-21 released can be affected by epigenetic modifications. For instance, it has been found that in CD4+ T cells belonging to individuals with relapsing-remitting Multiple Sclerosis, the over-methylation of the MIR21 gene led to a lower production of miR-21 as well as increased activity of numerous target genes [43], [44].

Autophagy, a term which means "self-digestion," was initially put forward in the 1950 s and was more closely examined by de Duve and Wattiaux in regards to the livers of animal subjects afterwards [18], [45]. Since the lysosomes were discovered, the concept of autophagic degradation has been acknowledged, but in-depth research into the autophagic processes is of more recent times. Autophagy is an orderly, homeostatic procedure through which various components of the cell cytoplasm are seized and broken down to generate an energy source and replace amino acids in moments of metabolic tension [46], [47]. The autophagy process involves three distinct stages: first, the autophagy-associated gene (ATG) triggers the building of phagophores with omegasome, an architecture generated by the endoplasmic reticulum, in the cytoplasm. The phagophores form an autophagosome, which contains two membranes, by engulfing the material inside the cell destined for autophagy, and expanding and merging them together. Subsequently, lysosomes and autophagosomes advance towards one another, and the exterior membrane of the autophagosome attaches to a lysosome with the support of soluble N-ethylmaleimide-sensitive factor attachment protein receptor. The autophagosome and lysosome combine to form an autophagolysosome, thereby releasing the material from the autophagosome into the lysosome for breakdown caused by the acidity and hydrolysis inside the lysosome [48], [49], [50], [51].

A multitude of proteins acting in tandem are instrumental in stimulating the growth and broadening of the double membrane structure of autophagosomes. This process is separated into three sections: the beginning caused by inhibition of mammalian target of rapamycin (mTOR), the formation of nucleus confirmed with beclin1 and the class III phosphatidylinositol 3-kinase (PI3K) complex, and the extension secured by the microtubule-associated protein light chain 3 (LC3) [45], [52], [53], [54]. When particular nutrients, particularly amino acids, are present, or when insulin is increased because of the intake of nutrients, PI3K receptor type I is activated, resulting in the activation of both the Akt and mTOR pathways. This signaling will inhibit autophagy since mTOR is recognized as a protein that keeps Atg1 from interacting with its related proteins like Atg13 and Atg17 [55]. The Atg1-Atg13-Atg17 complex assembles other molecules so that autophagosomes can be formed [56], [57]. Rapamycin, a drug that inhibits the mTOR enzyme, is the most commonly used to trigger autophagy. Nevertheless, since mTOR can influence other processes and cells too, the conclusions drawn from experiments utilizing rapamycin do not always give a precise portrayal of its effect on autophagy [58].

The Atg1-Atg13-Atg17 complex is responsible for making the beclin1 and Vps34 proteins of the class III PI3K pair up on a membrane composed of fat molecules [59], [60]. This specific PI3K is distinct and has an alternate way of working as compared to class I PI3K which is triggered to initiate the mTOR enzyme in the presence of insulin. Moreover, the drug 3-methyladenine is specially formulated to block the activity of Vps34, which is part of the autophagy process [61]. The protein Beclin1 forms a complex with bcl2 and bcl-XL in order to stop autophagy, and the activity of this mechanism is regulated by c-Jun N-terminal kinase 1 through applying a phosphorylation process to bcl2 [62].

The establishment and enlargement of autophagosomes require the involvement of a third technique that combines two distinct ubiquitin-like proteins. This process initially necessitates the cooperation of Atg7 and Atg10 in order to unite Atg12 and Atg5 [63], which interacts with Atg16 [64]. The Atg12-Atg5 complex affixes itself to the membrane and later releases from the autophagosome. Subsequently, the Atg8 or LC3 protein undergoes a second conjugation reaction, and Atg4 cleaves off the C-terminal domain of LC3 leaving behind a glycine residue. At last, the activities of Atg7 and Atg3 bring about the joining of LC3I with phosphatidylethanolamine on the membrane, generating LC3II [65]. The LC3II binds the outer and inner walls of the autophagosome, facilitating expansion and closure of the membrane by the lipid-modified protein. After the autophagosome and lysosome merge, the LC3II is decomposed and its components are circulated into the cytoplasm, allowing the organism to remain in balance [66].