miR-146a is a key regulator of inflammation, myeloid cell proliferation, and cancer in mice. The study shows that targeted deletion of miR-146a leads to immune defects, including hyperresponsiveness to LPS, exaggerated inflammatory responses, and autoimmune disorders. miR-146a functions as a negative feedback regulator of the innate immune response by targeting TRAF6 and IRAK1, which are crucial for pro-inflammatory signaling. miR-146a-null mice develop autoimmune disease, characterized by splenomegaly, lymphadenopathy, and multiorgan inflammation, and are prone to premature death. Additionally, miR-146a-null mice exhibit myeloproliferation and tumor formation in secondary lymphoid organs, suggesting a tumor suppressor role. The study confirms that miR-146a regulates myeloid cell proliferation by controlling the expression of the M-CSF receptor (CSF1R). miR-146a also plays a role in preventing cancer by suppressing the growth of myeloid cells. The findings highlight miR-146a as a critical negative regulator of inflammation, myeloid cell proliferation, and cancer in the immune system.miR-146a is a key regulator of inflammation, myeloid cell proliferation, and cancer in mice. The study shows that targeted deletion of miR-146a leads to immune defects, including hyperresponsiveness to LPS, exaggerated inflammatory responses, and autoimmune disorders. miR-146a functions as a negative feedback regulator of the innate immune response by targeting TRAF6 and IRAK1, which are crucial for pro-inflammatory signaling. miR-146a-null mice develop autoimmune disease, characterized by splenomegaly, lymphadenopathy, and multiorgan inflammation, and are prone to premature death. Additionally, miR-146a-null mice exhibit myeloproliferation and tumor formation in secondary lymphoid organs, suggesting a tumor suppressor role. The study confirms that miR-146a regulates myeloid cell proliferation by controlling the expression of the M-CSF receptor (CSF1R). miR-146a also plays a role in preventing cancer by suppressing the growth of myeloid cells. The findings highlight miR-146a as a critical negative regulator of inflammation, myeloid cell proliferation, and cancer in the immune system.