MiRNAs (miRNAs) are small non-coding RNAs which are recognized as vital and evolutionarily ancient components of gene regulation [
1]. In the recent years, tremendous and growing studies have been focused on the role of mircoRNA (miRNA) in normal cellular as well as in disease processes, especially in cancer [
2,
3]. The expression profiling of miRNAs has already been used in cancer clinics as diagnostic and prognostic biomarkers to assess tumor development [
4]. The roles of various miRNAs were reported in different types of cancers, including breast, colon, gastric, lung, and prostate [
5‐
7]. Specifically, one type of miRNA is also involved in different cancers. For instance, the accumulating studies showed that the dysregulation of miR-199a is found in various cancers, including hepatocellular carcinoma [
8], ovarian cancer [
9], renal cell carcinoma [
10], osteosarcoma [
11] and etc. [
12,
13]. OS is the most common aggressive primary sarcoma of bone, which is usually occurred in children and adolescents [
14,
15]. Metastatic OS usually has poor prognosis in response to the current chemotherapy mainly due to the chemoresistance. However, little is known about the underlying mechanism that governs the chemoresistance of OS. To address this issue, we put our effects on elucidating the relationship between miRNAs and drug-resistance, and have found that several miRNAs are involved in OS drug resistance by targeting different genes [
16‐
19]. Notably, the previous report suggested that miR-199a-3p is down-regulated in OS [
11]. However, whether miR-199a-3p is involved in the OS drug resistance is still unknown. In this study, using a systematic analysis in the multi-drug sensitive (G-292 and U2OS) and resistant (MNNG/HOS) OS cell lines, we found that miR-199a-3p inhibits multi-drug resistance of OS. We further revealed that miR-199a-3p targets the AK4 gene, which was reported to be involved in stress, drug resistance, malignant transformation in cancer [
20‐
22]. Taken together, our findings provide a new mechanistic insight into OS drug resistance, which might give us hints for a rational design of the clinical therapy against OS.